Portable orthovoltage radiotherapy

ABSTRACT

A portable orthovoltage radiotherapy system is described that is configured to deliver a therapeutic dose of radiation to a target structure in a patient. In some embodiments, inflammatory ocular disorders are treated, specifically macular degeneration. In some embodiments, the ocular structures are placed in a global coordinate system based on ocular imaging. In some embodiments, the ocular structures inside the global coordinate system lead to direction of an automated positioning system that is directed based on the ocular structures within the coordinate system.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/912,557, filed Oct. 26, 2010, now U.S. Pat. No. 8,059,784, entitled,“PORTABLE ORTHOVOLTAGE RADIOTHERAPY”; which is a continuation of U.S.patent application Ser. No. 11/833,939, filed Aug. 3, 2007, now U.S.Pat. No. 7,822,175, entitled, “PORTABLE ORTHOVOLTAGE RADIOTHERAPY”;which claims priority benefit from U.S. Provisional Application No.60/933,220, filed Jun. 4, 2007, entitled, “PORTABLE ORTHOVOLTAGERADIOTHERAPY”; U.S. Provisional Application No. 60/922,741, filed Apr.9, 2007, entitled, “RADIATION THERAPY SYSTEM FOR THE TREATMENT OFMACULAR DEGENERATION”; U.S. Provisional Application No. 60/869,872,filed Dec. 13, 2006, entitled, “XRAY TREATMENT SYSTEM”; U.S. ProvisionalApplication No. 60/862,210, filed Oct. 19, 2006, entitled, “METHODS ANDDEVICE FOR NON-INVASIVE ROBOTIC TARGETING OF INFLAMMATORY LESIONS USINGRADIATION”; U.S. Provisional Application No. 60/862,044, filed Oct. 18,2006, entitled, “METHODS AND DEVICES FOR NON-INVASIVE ROBOTIC TARGETINGOF RETINAL LESIONS”; and U.S. Provisional Application No. 60/829,676,filed Oct. 16, 2006, entitled, “METHODS AND DEVICES TO APPLY FOCUSEDENERGY TO BODY REGIONS”; the entirety of each of which are incorporatedherein by reference.

BACKGROUND

1. Field of the Inventions

This disclosure relates to the treatment of ocular disorders usingtargeted photon energy. In particular, the present disclosure relates toan apparatus, systems, and methods for image-guided low energy x-raytherapy of ocular structures.

2. Description of the Related Art

Macular degeneration is a condition where the light-sensing cells of themacula, a near-center portion of the retina of the human eye,malfunction and slowly cease to work. Macular degeneration is theleading cause of central vision loss in people over the age of fiftyyears. Clinical and histologic evidence indicates that maculardegeneration is in part caused or results in an inflammatory processwhich ultimately causes destruction of the retina. The inflammatoryprocess can result in direct destruction of the retina or destructionvia formation of neovascular membranes which leak fluid and blood intothe retina, quickly leading to scarring.

Most treatments for macular degeneration are aimed at stopping theneovascular (or “wet”) form of macular degeneration rather thangeographic atrophy, or the “dry” form of Age-related MacularDegeneration (AMD). All wet AMD begins as dry AMD. Indeed, the currenttrend in advanced ophthalmic imaging is that wet AMD is being identifiedprior to loss of visual acuity. Treatments for macular degenerationinclude the use of medication injected directly into the eye (Anti-VEGFtherapy), laser therapy in combination with a targeting drug(photodynamic therapy); other treatments include brachytherapy (thelocal application of a material which generates beta-radiation).

SUMMARY

It would be advantageous to provide a treatment for ocular disorderswhich irradiates specific regions of the eye without substantiallyexposing the rest of the eye to radiation. In some embodiments describedherein, a radiotherapy system is disclosed that may be used to treat awide variety of medical conditions relating to the eye. For example, thesystem may be used, alone or in combination with other therapies, totreat macular degeneration, diabetic retinopathy, inflammatoryretinopathies, infectious retinopathies, tumors in the eye or around theeye, glaucoma, refractive disorders, cataracts, post-surgicalinflammation of any of the structures of the eye, ptyrigium, and dryeye.

In some embodiments described herein, radiotherapy (or externallyapplied radiation therapy) is used for treatment of maculardegeneration, and a standard treatment for macular degeneration isdisclosed. Radiotherapy for treatment of macular degeneration presentsseveral complications. For example, the eye contains several criticalstructures, such as the lens and the optic nerve, that can possibly bedamaged by excessive exposure to radiation. The application of externalbeam therapy is limited by devices and methodologies used to apply thetherapy. These devices and methodologies are older radiationtechnologies used to treat conditions such as tumors anywhere in thebody and were not developed specifically for ocular radiation therapy.In addition, logistics are difficult as far as patient recruitment andadministration of treatments because such treatment devices are borrowedfrom and displace oncologic therapies.

Retinal radiotherapy trials have shown stabilized or improved visualacuity without any significant toxicity. Radiation has also been shownto dry up neovascular membranes in patients and stabilize vision.However, due to limitations in the treatment of macular degenerationusing radiotherapy including localization of the region to be treated aswell as specific application of the radiation to the region to betreated, retinal radiotherapy often irradiates the entire retina, whichis both unnecessary and possibly harmful.

Brachytherapy for wet AMD is also a powerful therapy to treat wet AMD(Neovista, Inc., Press Release, March 2007, the entirety of which isincorporated herein by reference). A major limitation of this treatmentis that it requires invasive procedures involving partial removal of thevitreous fluid of the posterior chamber of the eye to place thebrachytherapy probe. In addition, it cannot be fractionated because ofthe invasiveness required to deliver it. Furthermore, it would bedifficult to apply this therapy to patients who do not yet have visionloss because of the potential complications from the procedure.

Other diseases of the eye include glaucoma. In this disease, surgery isoften the second line of therapy after pharmaceutical therapy.Procedures such as trabeculoplasty, trabeculotomy, canaloplasty, laseriridotomy, placement of shunts, and other procedures all suffer from ashort-lived effect because of scar formation as a result of the surgicaltrauma. Anti-inflammatory drugs appear to offer a palliative and/orpreventative solution to the chronic scarring that occurs after theseprocedures; however, the drugs have to be given several times per dayand are associated with their own side effect profile such as seepageinto unwanted regions of the eye. Radiation (10 Gy) can be beneficial inthe prevention of scarring after glaucoma surgery (Kirwan, et. al.,Effect of Beta Radiation on Success of Glaucoma Drainage Surgery inSouth Africa: randomized controlled trial; British Medical Journal, Oct.5, 2006, the entirety of which is herein incorporated by reference).Capsular opacification is a common occurrence after cataract procedureswith placement of intra-ocular lenses. This scarring is caused by traumafrom the surgery, proliferation of lens cells, and materialincompatibility.

In some embodiments, the radiation treatment system is usedconcomitantly with laser therapy. That is, rather than using a lasersolely for pointing the x-ray device to the ocular target of choice, thelaser is used for both pointing and therapy. In these embodiments, thelaser preferably includes at least one additional energy or wavelengthsuitable for therapy of an ocular structure. The x-ray is preferablyapplied to the same region as the laser so as to prevent excessivescarring around the laser therapy.

In some embodiments of this disclosure, the electromotive and ocularimaging systems are utilized but laser therapy is the sole radiationenergy source used for treatment. In this embodiment, the ability of thesystem to focus radiation by passing the photons through the sclera fromdifferent angles to structures deep to the sclera can be utilized totreat diseases of the anterior chamber or posterior chamber with laserradiation while keeping the x-ray generation system off; indeed in someembodiments of the system, the x-ray generator is not included in thesystem. In these embodiments, the eye model, tracking, control, andfocusing systems for the x-ray therapy are utilized for therapeuticlaser therapy.

In certain embodiments, a device using a treatment planning system isdisclosed for providing targeted radiotherapy to specific regions of theeye. The treatment planning system integrates physical variables of theeye as well as disease variables from the physician to direct the x-raysystem to deliver therapy to the ocular structures. The device appliesnarrow beams of radiation from one or more angles to focus radiation toa targeted region in or on the eye. In certain embodiments, the devicemay focus radiotherapy to structures of the posterior eye, such as theretina. In certain embodiments, the device may focus radiotherapy tostructures of the anterior region of the eye, such as the sclera. Thetreatment planning system allows for planning of the direction of thebeam entry into the eye at different points along the sclera. The uniqueanatomy of each individual is integrated into the treatment planningsystem for accurate targeting, and in some examples, automatedpositioning of the x-rays of the device.

In some embodiments described herein, a treatment system is provided fordelivering radiation to a patient. The system preferably includes an eyemodel derived from anatomic data of a patient's eye, an emitter thatemits a radiation beam, and a position guide, coupled to the emitter,that positions, based on the eye model, the emitter with respect to alocation on or in the eye, such that the radiation beam is delivered toa target on or in the eye.

In some embodiments, the location comprises the target. The emitter canbe configured to deliver the radiation beam with a photon energy betweenabout 10 keV and about 500 keV or to deliver an radiation beamadjustable between about 25 keV and about 100 keV. In some embodiments,the radiation beam includes an x-ray beam. In some embodiments, thesystem further includes a planning module configured to determine, basedon the eye model, at least two of a beam target, a beam intensity, abeam energy, a beam trajectory, a treatment field size, a treatmentfield shape, a distance from the emitter to the target, an exposuretime, and a dose.

The position guide, in some embodiments, positions the emitter, based oninformation from the planning module, such that the emitter directs afirst radiation beam at a first position through a first portion of theeye to a treatment region within the eye. The position guide preferablypositions the emitter, based on information from the planning module,such that the emitter directs a second radiation beam at a secondposition through a second portion of the eye to the treatment regionwithin the eye. In some embodiments, the planning module is adapted toreceive input from a user, the input affecting an output of the planningmodule. In some embodiments, the system includes a sensing module thatsenses a position of the eye and relays information concerning theposition of the eye to the planning module.

The system includes, in some embodiments, a sensing module that senses aposition of the eye and relays information concerning the position ofthe eye to the position guide. The sensing module can include a portionthat physically contacts the eye, which can include a lens positionableon or over the cornea of the eye. The sensing module can, in someembodiments, optically sense the position of the eye with, for example,a laser.

In some embodiments, the system also includes a collimator thatcollimates the radiation beam to a width of from about 0.5 mm to about 6mm. The collimated beam can also have a penumbra of less than about tenpercent at a distance up to about 50 cm from the collimator. Theposition guide, in some embodiments, is configured to position theemitter, in use, at a first distance within 50 cm of the target, suchthat the emitter delivers the radiation beam to the target from thefirst distance. In some embodiments, a collimator is positioned, in use,to within about 10 cm of the target when the radiation beam is deliveredto the target.

The system can further include a detector that detects if the patient'seye moves such that the radiation beam is not directed to the target. Insome embodiments, the emitter is configured to automatically not emitthe radiation beam if the patient's eye moves out of a predeterminedposition or range of positions. Some embodiments include a laser emitterthat emits a laser beam that passes through a collimator and is directedtoward the eye.

Some embodiments described herein disclose a system for deliveringradiation to an eye that includes an eye model derived from anatomicdata of a patient's eye, an emitter that delivers an x-ray beam to theeye with an energy from about 10 keV to about 500 keV, a position guide,coupled to the emitter, that positions, based on the eye model, theemitter with respect to a location in or on the eye, to deliver thex-ray beam to a target in or on the eye, and a planning module thatdetermines at least two parameters of treatment based on the model ofthe eye. In some embodiments, the at least two parameters include two ofa beam target, a beam intensity, a beam energy, a beam trajectory, atreatment field size, a treatment field shape, a distance from theemitter to the target, an exposure time, and a dose.

The position guide, in some embodiments, is configured to direct a firstx-ray beam from a first position to a first region of a sclera of theeye to target a region of the eye, and is further configured to direct asecond x-ray beam from a second position to a second region of thesclera to target substantially the same region of the eye. In someembodiments, the region of the eye is at least one of the macula, thesclera, the trabecular meshwork, and a capsule of the lens of the eye.

The system can further include a collimator that collimates the x-raybeam. In some embodiments, the collimator is configured to collimate thex-ray beam to a width of from about 0.5 mm to about 6 mm, and in someembodiments, the system is configured to produce an x-ray beam having apenumbra of less than about five percent within a distance, from thecollimator to the target, of about 50 cm. The emitter, in someembodiments, is configured to deliver an x-ray beam with a photon energybetween about 25 keV and about 150 keV. In some embodiments, thecollimator is positioned, in use, to within about 10 cm of the targetwhen the x-ray beam is delivered to the target.

In some embodiments, a treatment system for delivering radiation to ahuman being is provided, the system including an eye model derived fromanatomic data of a patient's eye; an emitter that delivers an x-ray beamto the eye; and means for positioning the emitter, with respect to alocation on or in the eye, to deliver the x-ray beam to a target on orin the eye, the means being coupled to the emitter, and the positioningof the emitter being based on the eye model.

Some embodiments provide a treatment system for delivering radiation toa patient that includes an emitter that generates an radiation beam, anda position guide, coupled to the emitter, operable to positions theemitter with respect to a location on or in the eye, to deliver theradiation beam to a target on or in the eye, wherein the emitter isplaced within 50 cm of the target. In some embodiments, the systemfurther includes a collimator coupled to the emitter, the collimatorbeing placed, in use, to within 10 cm of the target when the emitteremits the radiation beam. In some embodiments, the system furtherincludes a collimated laser emitter that is coupled to the emitter.

In some embodiments described herein, a method of treating maculardegeneration of an eye is disclosed. The method preferably includesproviding a model of an eye of a patient with anatomic data obtained byan imaging apparatus, producing an x-ray beam with a width of from about0.5 mm to about 6 mm and having a photon energy between about 40 keV andabout 100 keV, and in some embodiments between about 40 keV and about250 keV, directing the x-ray beam such that the beam passes through thesclera to the retina of the eye, and exposing the retina to from about 1Gy to about 40 Gy of x-ray radiation.

In some embodiments, the method provides that at least one of the x-raybeam width, photon energy, and direction of the x-ray beam is determinedbased on the model of the eye. The method further provides, in someembodiments, that the retina is exposed to from about 15 Gy to about 25Gy of x-ray radiation. In some embodiments, treatment with the x-rayradiation can be fractionated, and a planning system can keep track ofthe quantity and location of prior treatments. In some embodiments, themethod includes reducing neovascularization in the eye by exposing theretina to the radiation. The method may further include administering tothe patient at least one of heating, cooling, vascular endothelialgrowth factor (VEGF) antagonist, a VEGF-receptor antagonist, an antibodydirected to VEGF or a VEGF receptor, microwave energy, laser energy,hyperbaric oxygen, supersaturate oxygen, ultrasound energy,radiofrequency energy, and a therapeutic agent, prior to, or after,exposing the retina to the radiation. The method further includes, insome embodiments, directing a first x-ray beam to pass through thesclera to the retina from a first position external to the eye, anddirecting a second x-ray beam to pass through the sclera to the retinafrom a second position external to the eye. In some embodiments, thex-ray beam is directed to pass through a pars plana of the eye. Thex-ray beam is, in some embodiments, directed to a macula of the eye.

Some embodiments herein describe a method of treating an eye of apatient that includes providing a model of the eye based on anatomicdata obtained by an imaging apparatus, producing a first x-ray beam anda second x-ray beam, each beam having a width of from about 0.5 mm toabout 6 mm, directing the first x-ray beam such that the first beampasses through a first region of a sclera of the eye to a target of aretina, and directing the second x-ray beam such that the second beampasses through a second region of the sclera to substantially the sametarget of the retina as the first beam, wherein the first region andsecond region of the sclera through which the first beam and second beampass are selected based on the model of the eye.

In some embodiments, a trajectory of the first beam is determined basedon the model of the eye, and in some embodiments, the directing of thefirst x-ray beam and the directing of the second x-ray beam occursequentially. In some embodiments, the first x-ray beam and the secondx-ray beam have photon energies of from about 25 keV to about 100 keV.Centers of the first and second x-ray beams, in some embodiments, areprojected through a point on the sclera at a distance of from about 0.5mm to about 6 mm from a limbus of the eye. In some embodiments, themethod further includes administering to the patient at least one ofheating, cooling, VEGF antagonist, a VEGF-receptor antagonist, anantibody directed to VEGF or a VEGF receptor, microwave energy,radiofrequency energy, laser energy, and a therapeutic agent, prior to,concurrently with, or subsequent to the directing of the first x-raybeam. The x-ray beam, in some embodiments, is produced by an x-raysource positioned less than about 50 cm from the retina. In someembodiments, the x-ray beam is emitted from a source having an end thatis placed within about 10 cm of the eye. In some embodiments, the retinais exposed to about 15 Gy to about 25 Gy in some embodiments, and, insome embodiments to about 35 Gy, of x-ray radiation during one treatmentsession.

Some embodiments described herein relate to a method of treating an eyeof a patient that includes providing a model of the eye based onanatomic data obtained by an imaging apparatus, producing a first x-raybeam and a second x-ray beam, each beam having a width of from about 0.5mm to about 6 mm, directing the first x-ray beam such that the firstbeam passes through a first region of the eye to a target within theeye, and directing the second x-ray beam such that the second beampasses through a second region of the eye to substantially the sametarget within the eye, wherein the first region and second region of theeye through which the first beam and second beam pass are selected basedon the model of the eye.

The target, in some embodiments, includes the lens capsule of the eye.In some embodiments, the target includes the trabecular meshwork of theeye or a tumor. In some embodiments, the first region comprises thecornea of the eye. In some embodiments, the first x-ray beam and thesecond x-ray beam have photon energies of from about 25 keV to about 100keV. In some embodiments, the first and second x-ray beams arecollimated by a collimator positioned within 10 cm of the eye, and insome embodiments, the x-ray beams are produced by an x-ray sourcepositioned within 10 cm of the eye. The x-ray source can also bepositioned within 50, 40, and/or 10 cm of the eye.

In some embodiments, the first region of the eye includes a first regionof a sclera and the second region of the eye comprises a second regionof the sclera, and an edge-to-edge distance from the first region of thesclera to the second region of the sclera is from about 0.1 mm to about2 mm. In some embodiments, the first and second x-ray beams are directedfrom a nasal region external to the eye. Some methods further includealigning the center of the patient's eye with the x-ray radiotherapysystem. Some methods also include developing a plan to treat a macularregion using the model of the eye, wherein the first and second x-raybeams overlap at the macular region, and the first and second x-raybeams are collimated to from about 0.5 mm to about 6 mm.

Some embodiments described herein disclose a method of applyingradiation to the retina of a patient's eye, the method includinglocalizing the macula of the patient with an imaging device, linking themacula to a global coordinate system, and applying an external beam ofradiation to the macula based on the coordinate system.

Some embodiments described herein disclose methods, of applyingradiation to a patient's eye, that include obtaining imaging data of atleast a portion of a patient's eye; identifying, based on the imagingdata, a location of a macula of the patient's eye; identifying a firstlocation of a fiducial marker located in or on the eye; mapping thelocation of the macula, relative to the first location of the fiducialmarker, in a coordinate system, thereby producing a mapped location ofthe macula in the coordinate system; positioning, based on the mappedlocation of the macula, a radiation source that applies radiation to themacula; and emitting the radiation from the positioned radiation sourceto the macula.

In some embodiments, a contact lens that contacts the sclera and/or thecornea of the patient comprises the fiducial marker. The positioning ofthe radiation source is automated, in some embodiments, based on thecoordinate system. The methods may also include repositioning theradiation source based on a movement of the fiducial marker to a secondlocation of the fiducial marker. In some embodiments, the methodsinclude, after the repositioning of the radiation source, emitting anadditional radiation beam from the radiation source to the macula.

In certain embodiments, after mapping the location of the macula,methods include detecting a movement of the eye. The methods also mayinclude determining a relative relationship between a new location ofthe macula and the coordinate system after the detecting of the eyemovement. Some embodiments further include relaying information aboutthe new location of the macula to a positioner that changes a positionof the radiation source, and in some embodiments, applying the radiationto a region of drusen in the eye.

In some embodiments, the emitting the radiation comprises emitting aradiation beam. Some embodiments further include applying at least oneadditional radiation beam to the macula. In some embodiments, theradiation beam and the at least one additional radiation beam areapplied simultaneously. In certain embodiments, the radiation beam andthe at least one additional radiation beam are directed such that theyintersect within a volume of tissue that includes the macula. Theobtaining imaging data of the retina, in some embodiments, includes atleast one of triangulation, interferometry, and phase shifting. In someembodiments, the imaging data is obtained with at least one of computedtomography, magnetic resonance imaging, optical coherence tomography,and positron emission tomography.

Described herein are methods, of applying radiation to a patient's eye,that include obtaining imaging data of at least a portion of a patient'seye; identifying, based on the imaging data, a location of a macula ofthe patient's eye; identifying a first location of an anterior structureof the eye; mapping the location of the macula, relative to the firstlocation of the anterior structure of the eye, in a coordinate system,thereby producing a mapped location of the macula in the coordinatesystem; positioning, based on the mapped location of the macula in thecoordinate system, a radiation source to apply a dose of radiation tothe macula; and emitting a radiation beam from the positioned radiationsource to the macula.

In certain embodiments, the anterior structure of the eye includes thesclera, and in some embodiments, the anterior structure of the eyeincludes at least one of a cornea, an anterior chamber, an iris, aconjunctiva, a pupil, an iridocorneal angle, a trabecular meshwork, alens capsule, a prosthetic intraocular lens, a ciliary body, a ciliarymuscle, a limbus, a pars plana, a scleral spur, and a lens of the eye.

Some embodiments further include repositioning the radiation sourcebased on a movement of the anterior structure to a second location ofthe anterior structure. Certain embodiments further include, after therepositioning of the radiation source, emitting an additional radiationbeam from the radiation source to the macula. In some embodiments,obtaining imaging data of the retina includes at least one oftriangulation, interferometry, and phase shifting.

Some embodiments provide a method of treating a region of an eye of apatient that includes producing an x-ray beam with a width of from about0.5 mm to about 6 mm and having a photon energy between about 40 keV andabout 250 keV, directing the x-ray beam toward the eye region, andexposing the region to a dose of from about 1 Gy to about 40 Gy of x-rayradiation, thereby treating the region of the eye.

In some embodiments, the method further includes providing a model ofthe eye with anatomic data obtained by an imaging apparatus, wherein atleast one of a width of the x-ray beam, a photon energy of the x-raybeam, and a direction of the x-ray beam is determined based on the modelof the eye. The region, in some embodiments, is exposed to from about 15Gy to about 25 Gy of x-ray radiation, and in some embodiments, theregion includes a retina of the eye. The treating can include reducingneovascularization in the eye by exposing the retina to the radiation,and/or substantially preventing progression from Dry Age-related MacularDegeneration (AMD) to neovascularization. In some embodiments, themethod also includes administering to the patient at least one ofheating, cooling, VEGF antagonist, a VEGF-receptor antagonist, anantibody directed to VEGF or a VEGF receptor, microwave energy,radiofrequency energy, a laser, a photodynamic agent, and a radiodynamicagent, and a therapeutic agent. Some embodiments further includedirecting a first x-ray beam to pass through a sclera to a retina from afirst position external to the eye, and directing a second x-ray beam topass through the sclera to the retina from a second position external tothe eye. The x-ray beam, in some embodiments, is directed through a parsplana of the eye, and in some embodiments, the x-ray beam is directed toa macula of the eye. The x-ray beam can also be directed through asclera of the eye to the macula of the eye.

Some embodiments provide that the dose is divided between two or morebeams, and in some embodiments, the dose is divided between two or moretreatment sessions, each of said treatment sessions occurring at leastone day apart. Some methods described herein further include determininga position of the eye relative to the x-ray beam during the exposing ofthe region to the x-ray radiation, and shutting off the x-ray beam ifthe position of the eye exceeds a movement threshold.

Some methods of treating an eye of a patient described herein includeproviding a model of the eye based on anatomic data obtained by animaging apparatus, directing a first x-ray beam such that the first beampasses through a first region of the eye to a target within the eye, anddirecting a second x-ray beam such that the second beam passes through asecond region of the eye to substantially the same target within theeye, wherein the first region and second region of the eye through whichthe first beam and second beam pass are selected based on the model ofthe eye, and assessing a position of the eye during at least one of theadministration of the first x-ray beam to the target, administration ofthe second x-ray beam to the target, and a period of time betweenadministration of the first x-ray beam to the target and administrationof the second x-ray beam to the target.

Some methods provide that the assessing occurs during administration ofthe first x-ray beam to the target, and some methods further includeceasing or reducing administration of the first x-ray beam when the eyemoves beyond a movement threshold. Some methods further includedirecting the second x-ray beam based on information from the assessingof the position of the eye.

For purposes of summarizing the disclosure, certain aspects, advantages,and novel features of the disclosure have been described herein. It isto be understood that not necessarily all such advantages may beachieved in accordance with any particular embodiment of the disclosure.Thus, the disclosure may be embodied or carried out in a manner thatachieves or optimizes one advantage or group of advantages as taughtherein without necessarily achieving other advantages as may be taughtor suggested herein.

BRIEF DESCRIPTION OF THE DRAWINGS

A general architecture that implements the various features of thedisclosure will now be described with reference to the drawings. Thedrawings and the associated descriptions are provided to illustrateembodiments of the disclosure and not to limit the scope of thedisclosure. Throughout the drawings, reference numbers are re-used toindicate correspondence between referenced elements.

FIG. 1A illustrates a side view of embodiments of a system for treatingthe eye using radiotherapy.

FIG. 1B is a schematic format of embodiments of a radiotherapy treatmentsystem.

FIG. 1C is a schematic of the eye.

FIGS. 1D and 1E depict embodiments of a radiotherapy system whichcommunicates with a lens on the eye.

FIG. 1F depicts an x-ray radiation spectrum.

FIG. 2A illustrates a side schematic view of embodiments of aradiotherapy system illustrating some system components of FIGS. 1A-B.

FIGS. 2B′-2B″″ illustrate several embodiments of various collimators.

FIG. 2C illustrates embodiments of a radiotherapy system targeting alocation within an eye for treatment.

FIG. 2D illustrates some embodiments of a radiotherapy system targetinga location within an eye for treatment.

FIG. 2E illustrates a schematic view of a radiotherapy system and amethod of clinical application of the system.

FIG. 3 depicts embodiments of a subsystem of a radiotherapy controlmodule.

FIG. 4 illustrates a side view of an eye wherein eye location is trackedaccording to certain methods.

FIG. 5 illustrates a representative geometric model of the eye used formodeling purposes.

FIG. 6 illustrates representative beam angles with respect to ananterior surface and geometric axis of the eye.

FIGS. 7A-7F illustrates representative simulations of radiation beamstraveling through an eye to reach a retina of the eye and a dose profilefor a target tissue.

FIG. 8 depicts the results of Monte Carlo simulation performed toanalyze the effect of different energies and doses on the structures ofan eye.

FIG. 9 depicts the results of Monte Carlo simulation performed toanalyze the effect of various treatment regimes on the variousstructures of the eye.

FIG. 10 depicts experimental results of thin x-ray beams travelingthrough a human eye to validate a Monte Carlo simulation model.

FIGS. 11A ¹-11B depict the results of thin x-ray beams penetratingthrough an ophthalmic phantom to investigate penumbra and dosagevariables.

DETAILED DESCRIPTION

The present embodiments include systems and methods for treating a humaneye with radiotherapy. Some embodiments described below relate tosystems and methods for treating macular degeneration of the eye usingradiotherapy. For example, in some embodiments, systems and methods aredescribed for use of radiotherapy on select portions of the retina toimpede or reduce neovascularization of the retina. Some embodimentsdescribed herein also relate to systems and methods for treatment ofglaucoma or control wound healing using radiotherapy. For example, insome embodiments, systems and methods are described for use ofradiotherapy on tissue in the anterior chamber following glaucomasurgery, such as trabeculoplasty, trabeculotomy, canaloplasty, and laseriridotomy, to reduce the likelihood of postoperative complications. Inother embodiments, systems and methods are described to use radiotherapyto treat drusen, inflammatory deposits in the retina that are thought tolead to vision loss in macular degeneration. Localization of a therapyto the drusen to treat the surrounding inflammation may prevent theprogression of dry and/or wet AMD. Alternatively, a laser therapeutic isapplied to the drusen in combination (adjuvant therapy) withco-localized x-ray radiation to substantially the same spot where thelaser touched down on the retina; the laser spot can create a localizedheating effect which can facilitate radiation treatment or the laserspot can ablate the region and the radiation can prevent furtherscarring around the laser spot. Such combination therapy can enhance theefficacy of each therapy individually. Similarly, adjuvant therapies caninclude x-ray radiotherapy in combination with one or morepharmaceuticals or other radiotherapy enhancing drugs or chemicalentities.

Radiation can have both a broad meaning and a narrow meaning in thisdisclosure. Radiation, as used herein, is intended to have its ordinarymeaning and is meant to include, without limitation, at least anyphotonic-based electromagnetic radiation which covers the range fromgamma radiation to radiowaves and includes x-ray, ultraviolet, visible,infrared, microwave, and radiowave energies. Therefore, planned anddirected radiotherapy can be applied to an eye with energies in any ofthese wavelength ranges.

Radiotherapy can refer to treatment of disease using x-ray radiation;however, in this disclosure, radiotherapy is intended to have itsordinary meaning and is meant to include, without limitation, at leastany type of electromagnetic radiation which uses photons to deliver anenergy as a clinical therapy to treat a disease. X-ray radiationgenerally refers to photons with wavelengths below about 10 nm down toabout 0.01 nm. Gamma rays refer to electromagnetic waves withwavelengths below about 0.01 nm. Ultraviolet radiation refers to photonswith wavelengths from about 10 nm to about 400 nm. Visible radiationrefers to photons with wavelengths from about 400 nm to about 700 nm.Photons with wavelengths above 700 nm are generally in the infraredradiation regions. Within the x-ray regime of electromagnetic radiation,low energy x-rays can be referred to as orthovoltage. While the exactphoton energies of orthovoltage varies, for the disclosure herein,orthovoltage refers at least to x-ray photons with energies from about20 KeV to about 500 MeV.

The global coordinate system refers to a physical world of a machine orroom. The global coordinate system is preferably a system relating amachine, such as a computer or other operating device, to the physicalworld or room that is used by the machine. The global coordinate systemcan be used, for example, to move a machine, components of a machine, orother things from a first position to a second position. The globalcoordinate system can also be used, for example, to identify thelocation of a first item with respect to a second item. In someembodiments, the global coordinate system is based on a one-dimensionalenvironment. In some embodiments, the global coordinate system is basedon a two-dimensional environment, and in some embodiments, the globalcoordinate system is based on three or more dimensional environments.

Kerma, as used herein, refers to the energy released (or absorbed) pervolume of air when the air is hit with an x-ray beam. The unit ofmeasure for Kerma is Gy. Air-kerma rate is the Kerma (in Gy) absorbed inair per unit time. Similarly, “tissue kerma” rate is the radiationabsorbed in tissue per unit time. Kerma is generally agnostic to thewavelength of radiation, as it incorporates all wavelengths into itsjoules reading.

The beam shape is generally set by the last collimator opening in thex-ray path; with two collimators in the beam path, the secondarycollimator is the last collimator in the beam path and can be called the“shaping collimator.” The first collimator may be called the primarycollimator because it is the first decrement in x-ray power andgenerally is the largest decrement of the collimators; the secondcollimator can generally set the final shape of the x-ray beam. As anexample, if the last collimator opening is a square, then the beam shapeis a square as well. If the last collimator opening is circular, thenthe beam is circular. In some embodiments, there is one collimator whichserves as the primary collimator as well as the beam shaping collimator.

The penumbra refers to the fall-off in dose outside of the area of thelast collimator and beam shape and size set by that collimator,typically measured at some distance from the last collimator. Penumbra,as used herein, has its ordinary meaning, which is meant to include,without limitation, the percentage of radiation outside the area of thelast collimator when the x-ray beam reaches the surface of the eye orthe target within the eye, whichever structure is the one beingreferenced with respect to the penumbra. The penumbra can incorporatethe divergence of the beam as well as the scatter of the beam as ittravels through the air and through the tissue.

Ideally, the size of the primary beam is the same size as the lastcollimator to which the x-ray beam is exposed; that is, the penumbra isideally zero. In reality, a penumbra of zero is difficult to achievewhen the collimator is any distance from the target. However, thepenumbra can be optimized, for example, by the shape of the collimator,the material of the collimator, the processing of the collimatormaterial, the position of the anode of the x-ray tube, and the relativesizing of the collimator relative to the x-ray source. In someembodiments of the systems and methods provided herein, the penumbraarea percentage at the entry point to the eye is less than about 10%. Insome embodiments, the penumbra area percentage at the entry point to theeye is less than about 5%, and in some embodiments, the penumbra areapercentage is less than about 1%.

The penumbra can also refer to the percentage of radiation outside thezone of the shaping collimator at a target region of the macula. In someembodiments, the penumbra at the macula is less than about 40% and insome embodiments, the penumbra at the macula is less than about 20%, andin some embodiments, the penumbra at the macula is less than about 10%or less than about 5%. The penumbra can be incorporated into a treatmentplan; for example, predictive knowledge of the penumbra can be utilizedto plan the treatment. In one example, a finely collimated beam (e.g.,having a 4 mm diameter) is applied to the sclera. The beam at the retinacan be 5 mm (25% penumbra) or 6 mm (50% penumbra) diameter sufficientfor coverage of a lesion. With this method, the structures of theanterior eye are minimally irradiated while the lesion at the retina isfully covered. In this embodiment, divergence of the x-ray beam isutilized for minimizing the exposure of the front of the eye withoutsacrificing a therapeutic dose to the retina.

A related definition is that of “isodose fall-off” which refers to thedose fall-off independent of divergence angle of the beam. For example,in an ideal setting where there is no divergence angle, the isodose falloff is the same as penumbra. When divergence angle is introduced, theisodose fall-off is different from the penumbra, referring to thefall-off of dose around the shaping collimator beam without accountingfor divergence angle. The isodose fall off is measured in Gy/mm, alinear distance from the edge of the collimator shape over a distance.Divergence angles typically follow a 1/R² relationship assuming thesource is a point source or close to a point source. Divergence angle ishighly predictable for photons and can be calculated independently ofscatter and the other physics which go into Monte Carlo simulations.

Photons with shorter wavelengths correspond to radiation with higherenergies. The higher-energy range of x-rays is generally in the MeVrange and is generally referred to gamma x-rays, independent of how theradiation was generated. X-ray photons with relatively shorterwavelengths are referred to as orthovoltage x-rays. Higher energyradiation with shorter wavelengths corresponds to deeper penetrationinto target tissue, which is the reason that most applications using MeVenergies require extensive shielding of the patient and surroundings. Insome embodiments of this disclosure, x-rays typically used fordiagnostic purposes, or low energy orthovoltage x-ray sources, can beused for therapy of ocular diseases and/or disorders which arerelatively superficial in the patient such as breast, intra-operativeradiation application, skin cancers, and other disorders such asperipheral vascular disease, implants, etc. X-rays typically used fordiagnosis can be used for therapy by tightly collimating the x-ray beaminto a thin beam of x-ray photons and directing the beam to thesuperficial region to be treated. If the disorder is deeper than severalcentimeters inside the body, then higher energy sources (e.g., MeV) maybe preferred to enhance penetration of energy to the disorders. It isdifficult to collimate MeV x-ray beams to small diameters with smallpenumbras because their very high speed photons cause secondaryinteractions with tissue including generation of secondary x-rays andother radiations. X-rays with energies lower than 500 KeV and even lowerthan 200 KeV can more appropriately be collimated to very smalldiameters.

“Laser” energy is also composed of photons of different energies rangingfrom short wavelengths, such as ultraviolet radiation, up to longwavelengths, such as infrared radiation. Laser refers more to thedelivery mechanism than to the specific wavelength of radiation. Laserlight is considered “coherent” in that the photons travel in phase withone another and with little divergence. Laser light is also collimatedin that it travels with relatively little divergence as is proceeds inspace (penumbra). Light can be collimated without being coherent (inphase) and without being a laser; for example, lenses can be used tocollimate non-x-ray light. X-ray light is typically collimated with theuse of non-lens collimators, the penumbra defining the degree ofsuccessful collimation. Laser pointers are typically visualizationtools, whereas larger, higher-flux lasers are utilized for therapeuticapplications. In some embodiments, optics can be used, such as lenses ormirrors, and in some embodiments, there are no intervening opticalelements, although collimators may be used.

The two eye chambers are the anterior and posterior chambers. Theanterior chamber includes the lens, the conjunctiva, the cornea, thesclera, the trabecular apparatus, the ciliary bodies, muscles, andprocesses, the iris, etc. The posterior chamber includes the vitreoushumor, the retina, and the optic nerve.

“Ocular diseases,” as used in this disclosure, is intended to have itsordinary meaning, and is meant to include at least disease of theanterior eye (e.g., glaucoma, presbyopia, cataracts, dry eye,conjunctivitis) as well as disease of the posterior eye (e.g.,retinopathies, age related macular degeneration, diabetic maculardegeneration, and choroidal melanoma).

Drusen are hyaline deposits in Bruch's membrane beneath the retina. Thedeposits are caused by, or are at least markers of inflammatoryprocesses. They are present in a large percentage of patients over theage of 70. Although causality is not known, drusen are associated withmarkers of the location where inflammation is occurring and whereneovascularization has a high likelihood of occurring in the future;these are regions of so called “vulnerable retina.” Therefore, applyinginflammation reducing radiation to the region may be beneficial to thepatient.

Radiation therapy has historically been marginally successful intreating disorders of the eye; for example, in a recent Cochranemeta-analysis review (Cochrane Database 2007 (2), the entirety of whichis incorporated herein by reference), the authors discussed the meritsof radiation therapy for AMD. Among their general conclusions was asfollows: ophthalmologists were reluctant to refer patients to theradiation oncologists for fear that they would lose their patients; itwas difficult to localize the radiation source because specific methodswere not used for the clinical protocol; and fractionation schemes anddosing was not standardized. Therefore, there is a great need for thesystems and methods described in this disclosure.

Brachytherapy described above appears to have a highly beneficial effectat least when combined with pharmaceutical therapy as an adjuvanttherapy. Brachytherapy definitively localizes the radiation dose to theregion to be treated and ensures that the dose is delivered at a highrate. However, brachytherapy is difficult to control as far as atreatment plan (e.g., the surgeon can hold the probe in a variety ofpositions for any given patient) and the brachytherapy source typicallycannot be turned off (e.g., strontium has a 29 year half-life).

Radiotherapy System

The Portable Orthovoltage Radiotherapy Treatment system (PORT) 10 inFIG. 1A can be configured to deliver anywhere from about 1 Gy to about40 Gy or from about 10 Gy to about 20 Gy to regions of the eye includingthe retina, sclera, macula, optic nerve, the capsular bag of thecrystalline or artificial lens, ciliary muscles, lens, cornea, canal ofschlemm, choroid, conjunctiva, etc. In some embodiments, the system canbe configured to deliver from about 15 Gy to about 25 Gy. In someembodiments, the system 10 is capable of delivering x-ray therapy in anyfractionation scheme (e.g. 5 Gy per day or 10 Gy per month or 25 Gy peryear) as the treatment planning system can recall which regions had beentreated based on the unique patient anatomical and disease features.These features and previous treatments are stored in the treatmentdatabase for future reference.

The system can also deliver different photon energies depending on thedegree of disease or the region of the eye being treated. For example,the x-ray generation tube can deliver from about 20 KeV photons to about40 KeV photons or to about 60 KeV photons, or to about 100 KeV photons.It may be desirable to use about 20 KeV to about 50 KeV photons forstructures in the anterior portion of the eye because these energieswill penetrate less whereas it may be desirable to utilize from about 60KeV to about 100 KeV photons or greater for structures in the posteriorregion of the eye for greater penetration to the retina. In someembodiments, the x-ray generation tube can deliver photons with photonenergies from about 10 keV to about 500 keV, from about 25 keV to about100 keV, from about 25 keV to about 150 keV, and/or from about 40 keV toabout 100 keV. In some embodiments, selection of the photon energy canbe based on diagnostic calculations, which can include a model of theeye created from anatomic data taken from the actual eye.

Although generally specific for the eye in this disclosure, PORT can beapplied to any superficial body structure within reach of orthovoltagex-rays or to structures accessible during surgical procedures. Forexample, in regions such as the breast, it may be desirable to usex-rays with energies greater than about 40 keV but less than about 200keV to reach the structures of interest. Other structures of interestinclude, for example, skin lesions, facial lesions, mucosal lesions ofthe head and neck, nails, muscles, soft tissues, anorectal regions,prostate, genital regions, joints, tendons, muscles, and the urogenitaltract.

PORT can be applied to specific structures within the eye while sparingothers because of its imaging systems, its modeling systems, and itsfinely-tunable collimators can provide precisely directed x-ray beamsthat can be targeted on specific structures within the eye with smallpenumbras (for example, 1-5 mm beams with less than 10% penumbra). PORTtherapy is also based on individualized, biometric representations ofthe eye which allows a personalized treatment plan to be created forevery patient.

As described above, orthovoltage generators, or other low energy x-raygenerators, allow for the system to be placed in a room withoutrequiring thick protective walls or other special shielding apparatus orspecial controls which would be prudent with devices generating x-rayswith photon energies greater than about 500 keV. Orthovoltagegenerators, or other low energy x-ray generators, are also more compactthan linear accelerators which allow them to be moved and directed withless energy from control motors as well as with less internal andexternal shielding. The lower energy x-ray generators also allow forsimpler collimation and beam directing schemes with small penumbras andtight collimation. In addition, in a scheme where it is desired to movethe x-ray source, much less energy is used to move the source todifferent positions, and the entire system is scaled down in size withlower energy x-ray sources.

In some embodiments, the radiotherapy system is used to treat a widevariety of medical conditions relating to the eye. For example, thesystem may be used alone or in combination with other treatments totreat macular degeneration, diabetic retinopathy, inflammatoryretinopathies, infectious retinopathies, tumors in the eye or around theeye, glaucoma, refractive disorders, cataracts, post-surgicalinflammation of any of the structures of the eye (e.g., trabeculoplasty,trabeculectomy, intraocular lenses, glaucoma drainage tubes, cornealtransplants, infections, idiopathic inflammatory disorders, etc.),ptyrigium, dry eye, and other ocular diseases or other medicalconditions relating to the eye.

The radiotherapy treatment system preferably includes a source, a systemto control and move the source, an imaging system, and an interface fora health care professional to input treatment parameters. Specifically,some embodiments of the radiotherapy system include a radiotherapygeneration module or subsystem that includes the radiation source andthe power supplies to operate the source, an electromotive controlmodule or subsystem which operates to control the power to the source aswell as the directionality of the source, a coupling module which linksthe source and control to the structures of interest (e.g., the eye),and an imaging subsystem; these modules are linked to an interface for ahealthcare professional and form the underpinnings of the treatmentplanning system. The terms “module” and “subsystems” can be usedinterchangeably in this disclosure.

FIG. 1A illustrates a side view of embodiments of a system 10 fortreating ocular diseases using radiotherapy. In the embodimentsillustrated, the radiotherapy treatment system 10 comprises aradiotherapy generation module or subsystem 110, a radiotherapy controlmodule or subsystem 120, an interface display 130, a processing module140, a power supply 150, a head restraint 160, and an imaging modulewith a camera 400.

In some embodiments, the radiotherapy device delivers x-rays to the eye210 of a patient 220. The power supply 150 preferably resides inside thesystem 10 or adjacent the system 10 (e.g., on the floor). In someembodiments, however, the power supply 150 can reside in a differentlocation positioned away from the system 10. The power supply 150 can bephysically coupled to the x-ray generator 110 (in a monoblockconfiguration) or can be uncoupled from the x-ray generator (e.g., thex-ray source moves independently of the power supply and is connectedthrough high power cables). In some embodiments, a cooling system forthe X-ray tube is also provided. The cooling system can be water or oilor air convection and can be attached or located a distance from theradiotherapy system 10.

Voltage can be wall voltage of about 110V or 220V (with assistance of atransformer) which can be used for the devices in the system shown inFIG. 1A. Currents to drive x-rays out of the device may be on the orderof 1 amp or lower down to about 50 mA or even about 5-10 mA. What isdesired of the power supply is that a high voltage be generated to drivethe electrons from the cathode in the x-ray tube to the anode of thex-ray; electron movement is performed within a vacuum inside the x-raytube. The high voltage (e.g., about 30,000-300,000 volts or higher) maybe desired to accelerate the electrons inside the vacuum. A secondcurrent is typically used with x-ray power supplies in order to generatethe electrons from a filament, the electrons are subsequentlyaccelerated through the voltage potential. Therefore, x-ray powersupplies typically have two power supplies in order to generate x-rays.Once generated, the electrons speed toward the anode under the influenceof the high voltage potential; the anode is where the x-ray generatingmaterial typically rests (e.g., tungsten, molybdenum).

Once the electrons strike the x-ray generating material target, x-raysare generated. An absorbing metal (e.g., aluminum, lead, or tungsten)within the casing of the system of FIG. 1A will absorb much of thegenerated x-rays which have been scattered from the source 110. Thex-rays, which are pre-planned to escape, are emitted from the source andtravel into a collimator (e.g., a primary or secondary collimator) andoptionally through a filter (e.g. an aluminum filter). The collimator isintended to direct the x-rays toward the patient 220. Notably, asdescribed herein, collimators can be designed and manufactured so as tominimize penumbra formation and scatter and to optimize the shape and/ordirection of the x-ray beam. The power supply is preferably connected tothe x-ray source by a high power cable that is highly insulated toprevent power leakage.

The collimator can be one or more collimators (e.g., a primary 1030 anda secondary collimator 1040, and even a third collimator 1052, asillustrated in FIG. 2A). In some embodiments, a secondary (shaping)collimator is placed close to the eye 1300 (e.g., within 10 cm) of thepatient, and the primary collimator 1030 is placed close to the source1070. This type of configuration can decrease the penumbra generated bythe source 1070 on the ocular structures 1300.

In some embodiments, collimators are specialized apertures. Theapertures can be adjustable; for example, the aperture can be adjustablefrom about 1.0 cm to about 0.5 mm or below 0.5 cm to about 0.01 cm. Insome embodiments, the aperture is adjustable (e.g., automatically ormanually by the operator of the machine) between about 0.5 mm and about7.0 mm. In some embodiments, the collimator is constructed fromtungsten, lead, aluminum, or another heavy metal. In some embodiments,the collimator has a cylindrical shape for the radiation to passthrough; in other embodiments, the collimator has a coned shape for theradiation to pass through. In some embodiments, the collimator aperturehas a rounded shape. In certain embodiments, the collimator has acurvilinear shape for the x-ray to pass through. In some embodiments,the collimator is cut using wire-EDM; in other embodiments, thecollimator path is cut and polished using a laser. The smooth contour ofthe collimator allows for minimal scattering as the radiation passesthrough the collimation apparatus. In some embodiments, the collimatorhas a region of thinner metal than another region so that the beam isrelatively modified but does not have a sharp contour.

In some embodiments (FIG. 2C), a light pointer 1410 (e.g., a laser beamemitted from a source 1450) is coupled to a collimator 1405, or behindthe collimator 1405, so that the light pointer 1410 is coincident withan x-ray beam 1400; the light pointer 1410 can indicate the position ona surface of an eye 1300 through which the radiation source enters bytracking angles of incidence 1420, 1430 of the collimator and x-raybeam. The collimator 1405 is preferably co-linear with the light source1450 which can act as a pointer to indicate the point on the eye throughwhich the radiation enters the eye 1300.

In some embodiments, a laser pointer 1210, illustrated in FIG. 2B′ sitson top of, or is coincident with the x-ray beam through the primary orsecondary collimator 1215. The laser pointer 1210 can be reflected off areflector 1220 that aligns the laser pointer 1210 with the collimatoropening 1216 such that the laser point 1210 strikes substantially thesame position of a surface beyond the collimator opening as does thex-ray 1200. The reflector 1220 can be a beam splitter, and the beamsplitter can be transparent to x-ray energy 1200. The laser pointer 1210can emit a wavelength that is detectable by the system camera 1460.Because the pointer is seen on the camera, the pointer indicates wherethe radiation beam enters the eye. The pointer 1410 can also serve as avisual verification that the x-ray source is powered on and directed inthe proper orientation with respect to the ocular structure, or targettissue 1480, of interest. With a second camera in the system, the angleof incidence of the laser pointer and the x-ray beam can be determined.

At least one camera 400, 1460 is included in the system to at leasttrack the eye in real time. In some embodiments, the camera 400, 1460images the eye with or without the x-ray source tracking device (e.g.,laser pointer) described above. The camera can detect the position ofthe eye and relate the direction of the x-ray and collimator system tothe position of the eye. An optional display 130 directed to theoperator of the radiotherapy system on the system 10 can depict theposition of the x-ray device in real time in some embodiments.

In another embodiment (FIG. 4), the camera 2055 detects the position ofthe eye and digitizing software is used to track the position of theeye. The eye is meant to remain within a preset position 2060; when theeye deviates from the position 2060 beyond a movement threshold, asignal 2090 can be sent to the radiation source 2000. As used herein,the term “movement threshold” is intended to have its ordinary meaning,which includes, without limitation, a degree or measurement that the eyeis able to move and still be within the parameters of treatment withoutshutting the radiation source 2000 off. In some embodiments, themovement threshold can be measured in radians, degrees, millimeters,inches, etc. The radiation source 2000 is turned off when the eye is outof position 2057 beyond the movement threshold, and the radiation sourceis turned on when the eye is in position 2054, or within the movementthreshold.

In some embodiments, a connection, or coupling, 162 extends from thesystem and contacts the eye 210 (FIGS. 1D-1E). The connection can be aphysical connection which can include an optical or other communicationbetween the system and the eye in addition to a mechanical connection.The physical connection 162 can serve several functions. For example, insome embodiments, the connection 162 is a mechanical extension whichallows the position of the eye to be determined because it is directlyapplied to the cornea or sclera. It also provides for inhibition of theeye so that the patient is more inclined to be compliant with keepingtheir eye in one position throughout the treatment. In addition, the eyecan be moved into a pre-determined position, in the case, for example,when the patient's eye has been paralyzed to perform the procedure.Finally, the physical contact with the eye can be used to protect thecorneal region using an ophthalmic lubricant underneath the physicalcontact device. The physical connection 162 from the cornea allows forpositioning of the eye with respect to the system.

The physical connection 162 to the eye from the radiotherapy system 10can contact the limbus 910 (also see FIG. 1C 308) around the eye or cancontact the cornea 920 or the sclera 930. The physical connection cancontain a suction type device 912 which applies some friction to the eyein order to move the eye or hold the eye in place with some force. Incertain embodiments, the connection 162 contacts the sclera when suctionis applied. The physical connection 162 can dock onto a scleral lens 940or a corneal lens which is inserted separately into or onto the eye;piece 160 then docks into or onto the scleral or corneal contact lens.Any of the materials of the physical connection can be transparent tox-rays or can absorb some degree of x-ray. The physical connection 162can help to stabilize the eye of the patient, preventing eye movementunderneath the lens. If a lubricant is inserted inside the lens, thelens can hold a gel or lubricant to protect the eye during theprocedure. The lens can also contain through holes which can provide thecornea with oxygen.

The physical connection 162 can be movable with respect to the remainderof the radiotherapy system; the physical connection 162 can be rigid,substantially rigid, or can contain a spring 165, which allowsflexibility in the axial or torsional direction. In some embodiments,the connection 162 is not mechanical at all but is an optical or othernon-contact method of communicating between a radiotherapy system and alens 940 positioned on the eye. The physical connection 162 can signifythe coordinate reference frame for the radiotherapy system and/or cansignal the movement of the device with respect to the eye. Connection162 can therefore assist in maintaining eye location in addition tomaintaining eye position by inhibiting movement of the patient. Physicalconnection 162 can contain radiotranmitters or features which can becaptured on a camera so that the eye can be located in three-dimensionalspace.

In some embodiments, the physical connection 162 to the eye is dockedinto position on the eye by the physician so that it identifies thecenter of the limbus and the treatment axis through its center. Theposition of the eye can then be identified and tracked using by theradiotherapy system. With knowledge of the center of the limbus incombination with the eye model, the radiotherapy system can then bedirected about the treatment axis and center of the limbus to deliverradiation to the retina.

X-ray source 110 can travel around a central axis 405 or a focal pointwithin the eye 210, such as, for example, illustrated in FIG. 1D byarrows 112. Alternatively, the x-ray source 110 can travel around afloating focal point as defined by the treatment planning system andvirtual model of the eye. A floating focal point is one anywhere in theeye as opposed to a fixed focal point such as the macula for example. Insome embodiments, the x-ray source can move with six degrees of freedomaround a fixed or moving axis. In some embodiments, the x-ray sourceremains fixed in one spot to treat an eye structure in the anteriorportion of the eye or even the posterior portion of the eye depending onhow large an area is to be treated and the dose required. In someembodiments, the x-ray source 110 focuses x-rays on a target by movingto different positions around the eye and delivering x-rays through thesclera at substantially different entry points on the sclera but eachx-ray beam reaching a substantially similar target within the eye. Insome embodiments, the x-ray source remains in one location, deliveringx-ray energy to and through the sclera and to regions within the eye,such as the retina and specifically the macula. In some embodiments, thex-ray source 110 is moved with five degrees of freedom, four degrees offreedom, three degrees of freedom, or two degrees of freedom. In someembodiments, the x-ray source 110 is stationary and the collimator ismoved or the eye or the patient is moved to project the beam todifferent regions of the eye. In some embodiments, the retina is treatedby maintaining the x-ray beam in one position with respect to thesclera. The x-ray source 110 can be moved automatically by a robotic armor manually by the operator of the system. The ultimatethree-dimensional position of the x-ray source 110 can be dictated bythe treatment plan which communicates between a model of the eye andwith the robotic arm to determine the position of the x-ray beamrelative to the eye.

In some embodiments, only a small amount of movement is required of thex-ray source to entirely treat a disease of the retina, such as maculardegeneration and/or diabetic macular edema. In these embodiments, sixdegrees of freedom can be applied to the x-ray source 110, but the rangeof each degree of freedom is preferably limited so that the movementsystem only travels within a volume of about 1000 cm³, 500 cm³, 100 cm³,or about 50 cm³. The speed of the robot within these volumes can bedefined such that the robot moves 0.5 cm/s, 1 cm/s, 3 cm/s, 5 cm/s.Because each fractional treatment dose is relatively short and appliedover a small distance, the robot can sacrifice speed and travel distancefor smaller size.

In some embodiments, it is a goal of the treatment system to deliverradiation therapy substantially through the pars plana region of the eye(see FIG. 1C). Pars plana 215 is the region of the eye between the parsplicata 218 and a peripheral portion of the retina 280, the ora serrata.The pars plana 215 region of the eye contains the fewest criticalstructures enroute from the sclera 260 to the retina 280. It istypically the region through which surgeons will inject pharmaceuticalsin order to inject drugs into the eye or to perform vitrectomies becausethe smallest risk of damage to ocular structures exists with thisapproach Likewise, radiotherapy can be delivered to the posterior regionof the eye through the pars plana region 215 to minimize the potentialfor damage to structures such as the lens, yet reaching regions such asthe fovea 240 and with minimal radiation reaching the optic nerve 275.The image-guided orthovoltage therapy described herein allows suchspecific treatment.

The central axis 300 of the eye is typically defined by the geometricaxis 300, but in some embodiments, it can be defined by the visual axis305; the visual axis of the eye is represented by a line 306 from thecenter of the fovea 305 through the center of the pupil. The geometricaxis 300 can be defined by a perpendicular straight line 300 from thecenter of the limbus 308 straight directly back to the retina; this axiscan also be referred to as the treatment axis. The limbus 308 istechnically the point where the cornea meets the sclera or visually thepoint where the pigmented region of the eye meets the white region ofthe eye. The pars plana angle 212 can be measured from the geometriccentral axis 300 and can range from about 10 degrees to about 50 degreesoff the central geometric axis 300. The visual axis 306 is the straightline from the center of the macula 240 and out the front of the eyethrough the center of the pupil 217. The pars plana 215 region of theeye can be related to the central axis 300 of the eye through an angle α212. In some embodiments, x-rays with a tight collimation (e.g., smallerthan about 6-8 mm in diameter) and a small penumbra (e.g., less thanabout ten percent at the sclera) enter the pars plana region 215 of theeye, avoiding some of the critical structures of the eye, to reachstructures which are to be treated, such as the retina. In someembodiments, during the treatment, the eye can be stabilized with theassistance of physical or mechanical restraint or by patient fixation ona point so that the x-rays enter the eye substantially only in the parsplana region 215.

In certain embodiments, the patient is stabilized with respect to theaxis of the eye. If the patient or device moves, then the camera detectsthe movement and turns the device off or closes a shutter over theregion the x-rays leave the device or the collimator. In someembodiments, the x-ray source 110 is moved about the eye to one or morepositions determined by a treatment planning system, deliveringradiation through the pars plana region 215 of the eye to reach theretina. The total dose is divided across different regions of the sclerabut penetrates through the pars plana 215 region to reach the desiredregion of the retina (for example, the macula or the fovea).

The head restraint 160 portion of the radiotherapy system 10 may be usedfor restraining the head of the patient 220 so as to substantiallystabilize the location of the patient's eye 210 relative to theradiotherapy treatment system 10. The physician applying the treatmentcan align the central axis 300 of the patient's eye with the x-raysource. The restraint 160 can maintain the patient's position during thetreatment. If the patient moves away from the restraint 160 or movestheir eyes from the restraint, then the x-ray machine can be turned off(gating) manually or automatically and the patient's positionreadjusted.

In general terms, the patient's head is maintained in position with thehead restraint 160 while the eye 210 is tracked by the imaging system400 and/or treatment planning system and the x-ray source 110 is movedso that the x-ray beam enters the eye through the pars plana region 215;the x-rays, therefore, penetrate to the target regions of the retina andcreate minimal damage on their way to the retina.

The treatment planning system 800 (FIGS. 1B and 2E) provides thephysician interface with the system 10. The treatment plan is developedbased on pre-treatment planning using a combination of biometricmodalities including an imaging subsystem that can include, for example,OCT, or optical coherence tomography, CT scans, MRI scans, and/orultrasound modalities. The information from these modalities areintegrated into a computer-generated virtual model of the eye whichincludes the patient's individual anatomic parameters (biometry) as wellas the individual's specific disease burden. The treatment plan isoutput, for example, on the interface display 130 module of theradiotherapy system 10. The physician can then use the virtual model inthe treatment plan to direct the radiation therapy to the disease usingthe radiotherapy system 10.

As used herein, “eye model” or “model of the eye” refers to anyrepresentation of an eye based on data, such as, without limitation, ananteroposterior dimension, a lateral dimension, a translimbal distance,the limbal-limbal distance, the distance from the cornea to the lens,the distance from the cornea to the retina, a viscosity of certain eyestructures, a thickness of a sclera, a thickness of a cornea, athickness of a lens, the position of the optic nerve relative to thetreatment axis, the visual axis, the macula, the fovea, a neovascularmembrane, and/or an optic nerve dimension. Such data can be acquiredthrough, for example, imaging techniques, such as ultrasound, scanninglaser ophthalmoscopy, optical coherence tomography, other opticalimaging, imaging with a phosphor, imaging in combination with a laserpointer for scale, and/or T2, T1, or functional magnetic resonanceimaging. Such data can also be acquired through keratometry, refractivemeasurements, retinal nerve-fiber layer measurements, cornealtopography, etc. The data used to produce an eye model may be processedand/or displayed using a computer. As used herein, the term “modeling”includes, without limitation, creating a model.

FIG. 1B depicts a schematic overview of the x-ray treatment system 10.For conceptual simplicity, the components of the system are depicted inthe four boxes. The overall treatment planning system 800 is depicted bythe background oval shape, depicting a global interconnect between thesubsystems. The treatment planning system 800 directs the foursubsystems toward treatment of the region indicated by the physician.The four subsystems in general terms include an x-ray subsystem 700, acoupling subsystem 500, an electromotive subsystem 600, and an imagingsubsystem 400. These subsystems or modules interact to provide anintegrated treatment to the eye of a patient.

The subsystems work together to coordinate the treatment planning system800. The treatment planning system (TPS) 800 also provides the interfacebetween the physical world of the eye, the physical components of thesystem, and a virtual computer environment which interacts with thephysician and treatment team and contains the specific patient anddisease information. The coupling system 500, primarily, and the imagingsystem 400, secondarily, help link the physical world and the virtualworld.

The virtual world contains a computer-generated virtual model of thepatient's eye 505 based on physical and biometric measurements taken bya health practitioner or the imaging system 400 itself. The computermodel 505 (FIG. 2D) in the virtual world further has the ability tosimulate the projection 510 of an x-ray beam 520 from a radiation source524 through an anterior region of the eye 515 to the structure 514 to betreated on or in the eye 514 based on different angles of entry into theeye. The model can also include important eye structures, such as theoptic nerve 512, to consider during the treatment planning process. Thevirtual world also contains the physician interface to control thedevice 524 and interface the device with respect to the physical world,or that of the actual physically targeted structure. After integratingthe inputs from the physician and modeling the beam angles and desireddirection to direct the therapy, the virtual world outputs theinformation to the electromotive subsystem to move the x-ray device tothe appropriate position in three-dimensional space. The couplingsubsystem 500 (in the physical world) can include a mechanism todetermine the angle of incidence of the x-ray beam with respect to thesurface of the eye using one or more laser or angle detectors, asdiscussed above.

In some embodiments, the coupling system 500 contains a camera 518 whichcan image a spot 516 on or in an eye. Information from the camera isthen preferably transferred to the virtual eye model 522 and again tothe motion and radiotherapy system 524. In certain embodiments, thecoupling system 500 is a physical connection with the eye. In someembodiments, the coupling system 500 is not a physical link but is acommunication link between a lens on the eye and a detection system. Forexample, a lens can be a communication beacon to relay eye position tothe system 500. In some embodiments, the lens can contain markers thatare imaged by the imaging camera 518, through which the next stage inthe therapy can be determined. In some embodiments, a combination ofthese techniques is used.

In some embodiments, the position of the eye and the x-ray source areknown at all times, and the angles of entry of the x-ray can thereforebe realized. For example, the central axis of the eye can be determinedand the x-ray source offset a known angle from the central axis. Thecentral axis, or treatment axis, in some embodiments can be assumed tobe the axis which is perpendicular to the center of the cornea or limbusand extends directly posterior to the retina, as discussed previously.Alternatively, the coupling subsystem can detect the “glint” orreflection from the cornea. The relationship between the glint and thecenter of the pupil is constant if the patient or the patient's eye isnot moving. If the patient moves, then the glint relative to the centerof the pupil is not in the same place. A detector can detect when thisoccurs, and a signal can be sent from the virtual world to the x-raydevice to turn the x-ray device off or to shutter the system off.

The actual acquisition method notwithstanding, the information obtainedfrom the coupling subsystem is preferably sent to the computer systemand to the virtual eye model. The imaging subsystem 400 captures animage of the eye in real time with a camera 1460 and feeds the data intothe software program that creates a virtual model of the eye. Incombination with the physical world coupling system 500, the predictedpath of the x-ray beam through the eye can be created on the virtualimage. Depending on the region to be treated, the electromotive systemand/or x-ray system can be readjusted; for example, a robot arm can movethe x-ray source 110 to a position to send a radiation or x-ray beam toa location on or in the eye based on the model of the eye as created bythe TPS and as captured by the imaging system 400.

In certain embodiments, the radiotherapy generation system 100 caninclude an orthovoltage (or low energy) radiotherapy generator as thex-ray subsystem 700, as discussed in further detail with reference toFIG. 1A, a schematic of the device. The radiotherapy generationsubsystem 110 generates radiotherapy beams that are directed toward theeye 210 of the patient 220 in FIG. 1A. In certain embodiments, theradiotherapy control module 120 includes an emitter 200 that emits adirected, narrow radiotherapy beam generated by the radiotherapygeneration subsystem 110. As used herein, the term “emitter” is intendedto have its plain and ordinary meaning, and the emitter can includevarious structures, which can include, without limitation, a collimator.In some embodiments, the control module 120 is configured to collimatethe x-ray beams as they are emitted from the radiotherapy generationsubsystem 110. The x-ray subsystem 700 can direct and/or filterradiotherapy rays emitted by the x-ray tube so that only those x-raysabove a specific energy pass through the filter. In certain embodiments,the x-ray subsystem 700 can include a collimator through which thepattern or shape of an x-ray beam is determined. The filtering of thesource preferably determines the amount of low energy inside the x-raybeams as well as the surface-depth dose as described in ensuing figures.In some embodiments, it is desirable to deliver orthovoltage x-rays witha surface-to-depth dose less than about 4:1 to limit dose accumulationat the surface of the eye. In some embodiments, it is desirable to havea surface-to-depth dose less than about 3:1 or 1.5:1 but greater thanabout 1:1 when using orthovoltage x-rays. Therefore, the radiotherapycontrol system can control one or more of the power output of the x-ray,the spectrum of the x-ray, the size of the beam of the x-ray, and thepenumbra of the x-ray beam.

In certain embodiments, the electromotive subsystem 600 of theradiotherapy system may move the x-ray source and the collimator todirect a narrow radiotherapy beam emitted from the x-ray source toirradiate specific regions of the patient's eye 210 by directing energyonto or into targeted portions of the eye 210, while at the same timeavoiding irradiation of other portions of the eye 210. For example, thesystem 10 may target a structure of the posterior region of the eye,such as the retina, or a structure on the anterior region of the eye,such as the trabecular meshwork, the sclera, the cornea, the ciliaryprocesses, the lens, the lens capsule, or the canal of schlemm. Thesystem 10 can deliver radiotherapy to any region of the eye, including,but not limited to, the retina, the sclera, the macula, the optic nerve,the ciliary bodies, the lens, the cornea, Schlemm's canal, the choroids,the capsular bag of the lens, and the conjunctiva.

In certain embodiments, the x-ray subsystem 700 can collimate the x-rayto produce a narrow beam of specified diameter and shape. For example,in certain embodiments using a collimator, the diameter of thecollimator outlet may be increased or decreased to adjust the diameterof the radiotherapy beam emitted by the collimator. In certainembodiments, the x-ray subsystem 700 can emit a beam with a diameter ofabout 0.1 mm to about 6 mm. In certain embodiments, the x-ray subsystem700 can emit a beam with a diameter of less than about 0.1 mm. Incertain embodiments, the x-ray subsystem 700 can emit a beam with adiameter of between about 0.5 mm and about 5 mm. As described in furtherdetail below, narrow beams and virtual models are useful to ensure thatthe energy is applied to a specific area of the eye and not to otherareas of the eye. In some embodiments (FIG. 2B′-2B′″), the radiationcontrol module can emit an x-ray beam with a circular 1212 ornon-circular 1214 shape; in some embodiments, the radiation controlmodule can emit an x-ray beam with a rectangular shape 1214 or a squareshape. In some embodiments, the radiation control module can emit anx-ray beam with an arc shape or an elliptical shape or a doughnutconfiguration 1217 through a circular collimator 1215 with an opaqueregion 1218 in the center. In some embodiment, the collimator 1215 caninclude a conical-shaped opening 1232, such as depicted in FIG. 2B″″,for providing a precisely shaped beam 1200.

In certain embodiments, the radiotherapy system 10 allows for selectiveirradiation of certain regions of the eye without subjecting other areasof the eye to radiation by using a narrow, directed treatment beam, thetreatment beam dictated by the specific anatomy of the patient's eye.For example, the radiotherapy control module 120 can direct radiotherapybeams generated by the radiotherapy generation module 110 to a patient'smacula, while substantially avoiding radiation exposure to otherportions of the patient's eye, such as the lens, the trabecularapparatus, and the optic nerve. By selectively targeting specificregions of the eye with radiation based on knowledge of the anatomy ofthe eye and linking the radiation system to the anatomy for treatmentpurposes, areas outside of the treatment region may avoid potentiallytoxic exposure to radiation. In some embodiments, the x-ray beam followsa trajectory 250 that enters the eye through the pars plana region 215which is a zone of the sclera 260 between the iris 270 and the retina260. By directing the beam to this region and limiting the penumbra orscatter of the beam using specialized collimators, the beam can belocalized onto an eye structure with minimal photon delivery to otherstructures of the eye, such as the cornea 255, the ciliary body andfibers 216 and other structures.

In certain embodiments, the radiotherapy treatment system 10 can includea shutter for controlling the emission of radiotherapy beams. Theshutter may comprise a material opaque to the radiation generated by theradiation generation module 110. In certain embodiments, a shutter maybe used to control the emission of beams from the radiotherapygeneration module 110. In certain embodiments, a shutter may be used tocontrol the emission of beams from the radiotherapy control module 120.In certain embodiments, the shutter may be internal to either of saidmodules 110 and 120, while in certain embodiments, the shutter may beexternal to either of said modules 110 and 120. In some embodiments, thesystem 10 is turned off to stop x-ray delivery, and in certainembodiments, the x-ray source 110 is turned off or its intensity turneddown to limit or stop x-ray delivery to the target. In certainembodiments, the shutter or aperture changes shape or size.

In certain embodiments, and as explained above with respect to FIG. 1A,the radiotherapy treatment system 10 can deliver radiotherapy beams fromone angle. In certain embodiments, the radiotherapy treatment system 10can deliver radiotherapy beams from more than one angle to focus thebeams on the treatment target. Certain embodiments of the system 10 thatcan deliver radiotherapy beams from more than one angle can include aplurality of stationary radiotherapy directing modules. The stationaryradiotherapy modules can be positioned in a wide variety of locations todeliver radiotherapy beams to the eye at an appropriate angle. Forexample, certain embodiments of the radiotherapy treatment system 10include five radiation source module-radiation directing module pairsthat are connected to the radiotherapy treatment system 10 in such a waythat they are spaced equidistantly around a circumference of animaginary circle. In this embodiment, the power supply could be aswitching power supply which alternates between the various x-raygenerators. Certain embodiments of the system 10 that can deliverradiotherapy beams from more than one angle can include moving theradiotherapy directing module. Certain embodiments of the system 10 thatcan deliver radiotherapy beams from more than one angle can includemoving the radiotherapy source using an electromotive subsystem 700(FIG. 1B), such as a robot.

In some embodiments of the present disclosure, orthovoltage x-rays aregenerated from the x-ray generation module 700. X-ray photons in thisorthovoltage regime are generally low energy photons such that littleshielding or other protective mechanisms can be utilized for the system10. For example, diagnostic x-rays machines emit photons withorthovoltage energies and require minimal shielding; typically, only alead screen is used. Importantly, special rooms or “vaults” are notrequired when energies in the orthovoltage regime are used. Diagnosticx-ray machines are also portable, being transferable to different roomsor places in the clinical environment. In contrast, linear acceleratorsor LINACS which typically deliver x-rays with energies in the MeV rangerequire thickened walls around the device because higher energy x-rayphotons have high penetration ability. Concomitant with the higherenergy photons, LINACS require much greater power and machinery togenerate these high energy photons including high voltage powersupplies, heat transfer methodologies, and internal shielding andprotection mechanisms. This increased complexity not only leads tohigher cost per high energy photon generated but leads to a much heavierdevice which is correspondingly more difficult to move. Importantly, asdescribed above and demonstrated experimentally below, MeV photons arenot necessary to treat superficial structures within the body and infact have many disadvantages for superficial structures, such aspenetration through the bone into the brain when only superficialradiation is required.

X-Ray Subsystem

The x-ray subsystem 700 generates x-rays and can include a power supply,a collimator, and an x-ray tube. In certain preferred embodiments, thex-ray subsystem 700 includes an orthovoltage x-ray generation system1070 to produce orthovoltage x-rays with energies between 10 KeV and 500KeV or even up to 800 KeV. This type of x-ray generation scheme is wellknown in the art and includes a high voltage power supply whichaccelerates electrons against a tungsten or other heavy metal target,the resulting collision then generating electromagnetic energy withx-ray energies.

Orthovoltage or low energy x-ray generators typically emit x-rays in therange from about 1 KeV to about 500 KeV or even up to about 1 MeV. Insome embodiments, the system described herein emits x-rays with photonenergies in the range from about 25 KeV to about 100 KeV. The use of lowenergy x-ray systems allow for placement of these x-ray treatmentsystems in outpatient centers or other centers and will not require theoverhead and capital requirements that high energy (MeV or gamma) x-raysystems require. In the treatment of ophthalmologic disorders, such asAMD, placement in the ophthalmologist office or close to theophthalmologic office is important because the ophthalmologists cantreat many more patients, a very important component when treating adisease that afflicts millions of patients. If the device were limitedto operating within vaults inside radiation oncology centers, the numberof treatable patients would be much more limited because of access,cost, competition with other diseases, and other logistics.

The radiation generation module in some embodiments is composed ofcomponents that are arranged to generate x-rays. For example, a powersupply generates current which is adapted to generate and accelerateelectrons toward an anode, typically manufactured from a heavy metalsuch as tungsten, molybdenum, iron, copper, nickel, or lead. When theelectrons hit one of these metals, x-rays are generated.

An exemplary set of x-ray spectra is shown in FIG. 1F. KVp refers to themaximum wavelength of the x-ray generated. For example, the 80 KVpspectra in FIG. 1F has a maximum of 80 KeV with a leftward tail of lowerenergy radiation. Similarly, the 60 KVp spectrum has a maximum of 60 KeVwith a similar leftward tail. All spectra in the figure have beenfiltered through 3 mm of Aluminum for filtering which shapes thespectral curve as lower wavelengths are filtered to a greater degreethan the higher wavelengths.

A power supply 150 as shown in FIG. 1A powers the radiation module. Thepower supply 150 is rated to deliver the required x-ray with a givencurrent. For example, if 80 KeVp x-rays are being delivered from thesource at 10 mA, then the power required is 800 W (80 kilovolts×0.01 A).Connecting the power supply to the x-ray source is a high voltage cablewhich protects and shields the environment from the high voltage.

The cable is flexible and in some embodiments has the ability to bemobile with respect to the power supply. In some embodiments, the powersupply is cooled with an oil or water jacket and/or convective coolingthrough fins or a fan. The cooling fluid can move through the device andbe cooled via reservoir outside the system 10.

Electromotive Subsystem

FIG. 2A depicts embodiments of the electromotive subsystem 600 of thetreatment system illustrated in FIG. 1B. The subsystem is anadvantageous component of the therapeutic system because it controls thedirection and the size of the x-ray beam. In general terms, theelectromotive subsystem is directed in the space of the globalcoordinate system 1150 by the personalized eye model created from thepatient's biometric data. The data from the model is transferred throughthe treatment planning system (TPS) to the electromotive subsystem 600to direct the x-ray beam to the target on or in the eye.

In certain embodiments, the system can include a collimation system, ashutter system, and an electromechanical actuation system to move thex-ray source and/or collimators. Referring to FIG. 2A, orthovoltagex-ray source 1070 is depicted. Collimators 1030, 1040, and/or 1052 arecalibrated to produce a small collimated beam 1062 of x-ray photons; ina preferred ophthalmic embodiment, the tightly collimated beam 1062 hasan area of from about 1 mm² to about 20 mm² in a circular or other shapeand a diameter of from about 0.5 mm to about 6.0 mm. Multiplecollimators allow for improved penumbra percentages; the smaller thepenumbra, the finer the application of x-rays to a specified structure.FIGS. 2B′-2B′″ depicts embodiments of collimator designs in which avariety of collimator configurations are depicted. For example, FIG.2B′″ depicts a collimator configuration in which a doughnut shape ofx-rays is generated; FIG. 2B″″ depicts a collimator configured with anozzle, or conical, shape 1232 to limit the penumbra or create asubstantially uniform radiation beam. The collimators, operating inconjunction with filters 1010, 1020 preferably cause the x-rays to leavethe collimator in a beam 1090 having a substantially parallelconfiguration.

The electromotive subsystem 1100 interacts with and is under thedirection of the global treatment planning system 800 in FIG. 1B. Theelectromotive subsystem 1100 receives commands from the treatmentplanning system 800 which can dictate among other things, the length oftime the x-ray machine is turned on, the direction of the x-ray beamwith respect to the eye target using data from the eye model ortreatment planning system, the collimator size, and the treatment dose.The eye target 1300 and the control system 1100 can be linked in globalcoordinate space 1150 which is the basis of the coupling system. Thetreatment planning system 800 directs the therapy using globalcoordinate system 1150. The x-ray control system 1100 dictates thedirection and position of the x-ray beam with respect to the oculartarget and moves the x-ray source into the desired position as a resultof commands from the treatment planning system 800.

In some embodiments, the collimators and/or the x-ray source can beplaced on a moving wheel or shaft (1100, 1110, 1120) with one or moremanual or automated degrees of freedom allowing the beam to be moved toa multitude of positions about the globe of the eye. In someembodiments, the x-ray source is movable with greater than one degree offreedom such as with a robot or automated positioning system. The robotmoves the x-ray source with respect to a global coordinate system suchas a cartesian coordinate system 1150 or a polar coordinate system. Theorigin of the coordinate system can be anywhere in physical space whichis convenient. In some embodiments, the x-ray source is movable withfour, five, or six degrees of freedom. In some embodiments, a robot isalso utilized to move any of the other components of the x-ray controlsystem such as the collimators. In some embodiments, the collimators arecontrolled with their own electromechanical system.

The electromotive subsystem can also contain one or more shutters toturn the beam on and/or off in an instant if desired (for example, ifthe patient were to move away). The x-ray source 1070 and/or collimatorscan move in any axis in space through an electromechanical actuationsystem (1100, 1110, 1120). In this embodiment, the treatment planningsystem can and then turning the device off when the eye is moved outsidethe target area.

The x-ray coupling subsystem 500 integrates with the x-ray generationsubsystem 700 under the umbrella of the treatment planning system 800.Also depicted in FIG. 2A and in more detail in FIG. 2C is at least onelaser pointer 1060 (1410 in FIG. 2C) which can serve multiple purposesas described. In some embodiments, the laser pointers 1060 couple withthe direction of the collimated x-ray beam 1090 so that the centroid ofthe laser beam is approximately identical to the centroid of the x-raybeam 1090 so as to have a visible marker as to where the x-ray beam isbeing delivered. Because x-rays are not visible, the laser pointersserve to identify the direction of the x-ray beam relative to otherparts of the radiotherapy system. Where the center of the x-ray beam ispointed, the center of the laser beam is correspondingly pointed as wellas shown in FIG. 2C.

Radiotherapy Coupling Subsystem

A third major subsystem of the present disclosure is the couplingsubsystem or module 500. In general terms, the coupling module 500coordinates the direction of the x-ray beam position to the position ofthe eye. As depicted in FIGS. 2A-2D, embodiments includes laser pointer1060 (one or more may be desired) that follows the direction of thex-ray beam. In some embodiments, the laser pointer(s) allow fordetection of the angles of incidence of the laser beam 1500 (FIG. 3)with respect to the sclera or other surface they impinge upon. Theangles of incidence 1510, 1520 can be defined by two orthogonal entranceangles (θ, φ) on the sclera or other surface. The centroids of the oneor more laser pointers 1070 coincide with the centroid of the x-ray beamas it impinges on the sclera or other surface.

As will be described in greater detail below, the laser pointer can alsoserve an important purpose in the imaging subsystem which is to providea visual mark (FIG. 3) 1570 on a surface of an eye 1600 when the eye isimaged by the camera 1550 and digitized or followed in the imagingsubsystem. With the visual mark 1570 on the digitized image and theangles of incidence 1510, 1520 of the laser beam 1500, computergenerated projections 1700, 1730 of the x-ray (or laser) can be producedon a computer-generated (virtual) retina 1720. In some embodiments, theprojections 1700, 1730 are the same, and in some embodiments, theprojections can be distinct. For example, in some embodiments, theprojection 1700 external to the eye may have different characteristics(e.g., trajectory, penumbra, etc.) than does the projection 1730 withinthe eye.

The computer-generated virtual retina 1720 (FIG. 3) is described infurther detail below and is a component of a virtual ocular model and isobtained via real data from an imaging system such as, for example, anOCT, CT Scan, MRI, A or B-scan ultrasound, a combination of these, orother ophthalmic imaging devices such as a fundoscopy and/or scanninglaser ophthalmoscopy. In addition to the retina, x-ray delivery to anystructure within the eye can be depicted on the virtual ocular model1725.

As shown in FIG. 3, laser beam 1500 is shown as the mark 1570 on screen1590, which is a depiction of the image seen by the camera 1550 and thenin digitized form within the treatment planning system 800. With anglesθ 1520 and φ 1510 and the location of the mark 1570 of the laser pointeron the digitized image of the eye 1600, the path 1730 through a “virtualeye” 1725 can be determined in a computer system 1710. If the positionis not correct, a signal can be sent back to the electromotive module inorder to readjust the targeting point and/or position of thelaser/x-ray.

In certain embodiments, a second camera can be used to so as to detectthe angles of the laser pointer and x-ray beam. These angles can be usedto detect the direction of the x-ray beam and send a signal to theelectromotive system for re-positioning. This feedback system can ensureproper positioning of the electromotive subsystem as well as correctdosing of the x-ray irradiation to the eye.

In some embodiments, an analogue system is used to detect the positionof the eye. In these embodiments, the target structure, the eye, isassumed to be in a position and the x-ray control system positions thex-ray source around the globe of the eye, then applying thepre-determined amount of radiation to the eye structure.

In certain embodiments, as depicted in FIG. 1E, a physical connection tothe eye is used for direct coupling between the eye and the radiotherapysystem. In these embodiments, a connection between the eye and thesystem can be mediated by a lens, such as a scleral or corneal contactlens 940. A physical link between the lens 940 and the system 10 is thenprovided by structure 175 which directly links to the radiotherapysystem 10. The scleral lens 940 can be a soft or hard lens. The lens 940can further contain one or more connections so that suction can beapplied to the sclera so as to stabilize the eye during the therapy. Thescleral lens 940 and associated attachments can be used to localize theeye in space. When the position of the sclera is known with the lens,the position of the eye is known as well. The eye is then coupled to theradiotherapy device 10. In some embodiments, the connection between thecontact lens and the radiotherapy device 10 is a non-mechanicalconnection in that the connection is an optical one such as with a laserpointer or one or more cameras to detect the actual position of the eyerelative to the radiotherapy system. The position of the eye in physicalspace is used to simulate the position of the beams in the virtual eyemodel and then back to the physical world to place the x-ray system todeliver the desired beam direction, angles, positions, treatment times,etc.

In some instances, it is desirable to know the scatter dose of the x-raybeam being delivered to a treated structure within the eye. For example,when neovascularization is being treated in the retina with a beamtraveling through the sclera, scatter to the lens or optic nerve may bemodeled. In further instances, it may be desired to know the dose to theneovascular membrane on the retina, the primary structure to be treated.

Imaging Subsystem

A fourth advantageous feature of the present disclosure is the imagingsubsystem 400, which can also serves as an eye tracking system (FIG. 4)and offers the ability to couple patient movement or eye movement withthe other subsystems above. This subsystem 400 advantageously ensuresthat the patient's eye 2010 does not grossly move out of the treatmentfield 2060. Camera 2055 can be the same camera 1550 in FIG. 3. Thecamera 2055 delivers an image to screen 2050. The imaged laser spot 2052is also shown on screen 2050. The video screen 2050 can be the samevideo screen 1710 in FIG. 3. Field 2060 in FIG. 4 is the zone withinwhich the eye can move; if the eye 2010 moves outside the zone 2060 onthe screen, then the radiation source is either turned off, shutteredoff, or otherwise disengaged from the eye 2010. In some embodiments,when an image of the eye 2030 reflects that the eye 2010 has moved outof field 2060, a signal 2090 is sent to the x-ray control system (FIG.2A) to turn the shutter off. Aside from ensuring that the eye remainswithin the treatment field, the imaging system couples to the othersubsystems by enabling projection of the laser pointer/x-ray beam 2052on the back of the computer generated virtual eye.

In some embodiments, the imaging subsystem is composed of two or morecameras which are used to create a three-dimensional rendering of theeye in space, the three-dimensional rendering then integrated into theoverall treatment scheme.

Treatment Planning System

The treatment planning system 800 is, in part, a virtual system and isdepicted in FIG. 1A; it integrates all of the inter-related modules andprovides an interface for the health care provider as well. The planningsystem 800 is the “brains” of the system 10 and provides the interfacebetween the physician prescribing the therapy and the delivery of thetherapy to the patient. The treatment planning system integratesanatomic, biometric, and in some cases, geometric assumptions about theeye “the virtual eye model” with information about the patient, thedisease, and the system. The information is preferably incorporated intoa treatment plan, which can then direct the radiation source to applyspecific doses of radiation to specific regions of the eye, the dosesbeing input to and output from the treatment planning system 800. Incertain embodiments of the treatment planning system 800, treatment withradiation may be fractionated over a period of days, weeks, or months toallow for repair of tissues other than those that are pathologic or tobe otherwise treated. The treatment planning system 800 can allow thephysician to map the treatment and dose region and to tailor the therapyfor each patient.

Referring to FIG. 2E, the treatment planning system 800 forms the centerof a method of treatment using radiosurgery system 10. In certainembodiments, the imaging module 400 of the system 10 includes an eyeregistration and imaging system 810. In certain embodiments, theeye-tracking system is configured to track patient movement, such as eyemovement, for use by the treatment planning system 800. The eye-trackingsystem 810 can calculate a three-dimensional image of the patient's eyevia physician inputs, and can include real-time tracking of movement ofthe patient's eye. The eye-tracking system obtains data that becomes afactor for determining radiotherapy treatment planning for a number ofmedical conditions relating to the eye, as described above. For example,the eye-tracking system may create an image of the posterior region ofthe patient's eye using the data it obtains. In certain embodiments, thedata can be transferred via cable communication or other means, such aswireless means, to the processing module 140 of the radiotherapytreatment system 10. In certain embodiments, the processing module 140may process data on the patient's eye and present an image of thepatient's eye on the interface display 130. In certain embodiments, theinterface display 130 may present a real-time image of the patient'seye, including movement of the eye.

In certain embodiments, the eye-tracking system obtains data on thepatient's eye while the patient's face is placed approximately uprighton and secured by the articulated head restraint 160 such that thepatient's eyes face substantially forward, in the direction of theimaging module 400. In certain embodiments, the eye-tracking system mayinclude an alignment system, adjustable using a joystick. The joystickcan be tilted horizontally, vertically, or both horizontally andvertically, on a fixed base, in order to adjust the location and/orimage displayed on the interface display 130 by the imaging module 400.

Another feature of the present disclosure is an integrated plan fortreatment. The scale of the device as well as a limitation that thedevice treat a specific anatomy limits the scope of the treatmentplanning system which also allows for economies of scale. It ispreferable that the x-ray beams be focused so that they apply radiationselectively to target regions of the eye and not to other regions of theeye to which high x-ray doses could be toxic. However, in someembodiments, the eye is the only anatomic region that is treated. Incertain embodiments, the retina is the target for the ophthalmictreatment system; one or more beams would be directed to regions of theretina as they pass through the sclera. For treatment planning purposes,it is preferable to know the three-dimensional position of the eye andretina with respect to the output beam of the system. The treatmentplanning system incorporates detailed images and recreates the geometryof the eye and subsequently directs the x-ray system to manipulate thex-ray output so that the output beam points in the target direction. Insome embodiments, the x-ray system is directed and moved automatically.

The treatment planning system 800 may utilize, or be coupled to, imagingsystems such as, for example, optical coherence tomography systems(OCT), ultrasound imaging systems, CT scans, MRI, PET, slit lampsmicroscopy systems, direct visualization, analogue or digitalphotographs (collectively referred to as Biometry Measurements 820). Insome embodiments, these systems are integrated into real-time feedbacksystems with the radiotherapy device such that second be second systemupdates of eye position and status can take place. Although relativelysophisticated, the system 800 would be limited to the ophthalmic regionand therefore takes advantage of specific imaging equipment onlyavailable for the eye.

In some embodiments, the treatment planning system incorporates theentire soft tissue and bony structures of the head of a patient. Themodel incorporates all the anatomic structures so that obstructinganatomic regions can be excluded from the treatment. For example, thetreatment plan incorporates the nose, the forehead, and associated skinand cartilage to dictate the directionality of the radiotherapy beamwith respect to the eye. In some embodiments, these structures arerelated to the global coordinate system and aid in tracking and treatingregions of the eye.

In some embodiments, the treatment planning system incorporates physicalmodeling techniques such as Monte Carlo (MC) simulation into thetreatment plan so that the real time x-ray doses can be delivered to theocular structures. In these embodiments, the inputs to the treatmentplanning system 800 are integrated with Monte Carlo simulation of theplanned treatment plan and the effects of the plan, both therapeutic andpotentially toxic, can be simulated in real time.

The method depicted in FIG. 2E is as follows. Biometry measurements 820and user controls 875 such as structure and dose are entered into thetreatment planning system 800. Other inputs include information from aneye registration and imaging system 810. The output from the treatmentplanning system 800 consists of commands sent to the x-ray source andelectromotive subsystem to move and position the source as well as todirect the on and off times (dose control) of the x-ray source 830.After a dose 840 is delivered, the treatment planning system 800 thensignals x-ray source movement to deliver an additional dose 840. Thiscycle can iterate several times until the treatment is completed.

For example, if a single beam can deliver the desired amount ofradiation, the treatment planning system determines the direction of thexray beam relative to the patient specific anatomy and then the xraysource is turned on. If two beams are desired to create the doseaccumulation to the target, then the treatment planning systemdetermines the size of the beams, their angles relative to the targetand the specific patient anatomy, then applies the first beam to the eyein a first angle and a second beam at a second angle relative to thetarget. A similar method is used for three, four, five, or six beams.

Monte Carlo Simulation and Experimental Validation

Monte Carlo (MC) simulation is the gold standard to model x-rayabsorption, scatter, and dosing to structures impinged on by the x-ray.Monte Carlo methods are a widely used class of computational algorithmsfor simulating the behavior of various physical and mathematicalsystems, and for other computations. They are distinguished from othersimulation methods (such as finite element modeling) by beingstochastic, that is, non-deterministic in some manner. Monte Carlosimulation forms an integral part of all treatment planning systems andis used to assist in treatment planning where radiation is involved.Monte Carlo simulation can also be used to predict and dictate thefeasibility and other elements of the radiotherapy system 10 (e.g.,optimization of the collimator and treatment planning schemes); forexample, the collimation designs, the energy levels, and the filteringregimes, can be predicted using Monte Carlo simulation. The designspredicted by Monte Carlo simulation should be experimentally verifiedand fine-tuned but MC simulation can predict the initial specifications.

In some embodiments, MC simulation is integrated into the treatmentplanning systems and in other embodiments, MC simulation dictates thealgorithms used by the treatment planning system 800. MC simulation isoften used in the back end of the treatment planning system to createboundaries of treatment. For example, MC simulation can predict thepenumbra of an x-ray beam. The penumbra of the x-ray beam is used in thevirtual world to direct the x-ray beam and set boundary limits for thex-ray beam with respect to the lens, optic nerve, etc.

In some embodiments, age-related macular degeneration (AMD) is thedisease treated with the x-ray generation system. In some embodiments,the x-ray system 10 is used to treat post-surgical scarring inprocedures such as laser photocoagulation and laser trabeculotomy orlaser trabeculectomy. In some embodiments, the x-ray system is used totreat ocular tumors. Importantly, the x-ray treatment system allows forselective irradiation of some regions and not others. In someembodiments, radiation is fractionated over a period of days, months, orweeks to allow for repair of tissues other than those which arepathologic or to be otherwise treated.

In order to A) prove that lower energy radiation can be delivered to theretina to treat AMD in a clinically relevant time period with a deviceon the size scale in FIG. 1, B) from a clinically relevant distance, andC) optimize some of the parameters of the treatment system for initialdesign specifications for the x-ray tube, an MC simulation wasperformed.

Eye geometry was obtained and a two-dimensional, then three-dimensionalmodel created, as shown in FIG. 5. Soft tissue and hard tissue (e.g.,bone 2060) was incorporated into the model in FIG. 5. FIG. 6 depictsdifferent beam angles (2100, 2110, 2120, 2130, 2140) which were modeledin this system to simulate therapy to the macula to treat AMD in thisexample. In this simulation, each beam enters the eye at a differentangle from the geometric center 2094, or treatment axis 2096, of theeye. Each beam cuts a different path through the eye and affectsdifferent structures such as the optic nerve 2085, lens 2075, sclera2076, cornea 2080, fovea 2092, etc. differently depending on the paththrough the eye. For example, beam 2120 enters the eye directly throughthe eye's geometric axis. A series of x-ray sources were modeled using arange of energies from 40 KeVp to 80 KeVp. A proposed collimation schemewas used to produce a near parallel beam as was a series of differentfilters (1-3 mm thickness aluminum). The combination of angle of entryof the beam, photon energy of the beam, and filtration of the beam allfactor into the relative amounts of energy deposition to the variousstructures.

FIGS. 7A-7E depict some of the results from the MC simulation showingthat the lower energy x-ray beams can indeed penetrate through thesclera 2200 and to the retina 2250 with minimal scatter to other ocularstructures such as the lens 2260. The higher density of dots indicateactual x-ray photons in the MC simulation so that the absence of photonson the lens for example (FIG. 7A) in certain beam angles is indicativeof lack of photon absorption at the level of the lens. These simulationsreveal that beams with widths from about 0.5 mm to about 8.0 mm willavoid critical structures of the anterior portion of the eye at certainangles off of the central axis.

FIG. 7F depicts the results of a simulation of a series of beams whichenter the eye through the pars plana region (FIGS. 7D-E). Thissimulation was done to minimize dose to the optic nerve with the beamsin 7D and 7E which minimize dose to the structures of the front of theeye. The beam shown in 7E has the most optimum profile with respect tothe optic nerve 2085 and lens 2260. Simulations with this beam areperformed by directing the beam toward the eye through the pars planadirection and from various directions a-g (FIG. 7F) which correspond tovarying nasal-temporal and caudal-cranial positions. In someembodiments, these beams are between 2 and 5 mm in diameter and have anenergy of between 60 KeV and 150 KeV.

In some embodiments, certain angles or directions are identified ascorresponding to certain structures that are desirable to avoid duringtreatment. Consequently, the angles that correspond to these structuresare not used for the trajectory of the x-ray during treatment, thusavoiding the optic nerve. For example, in some embodiments, the angle bmay correspond with an x-ray trajectory that would pass through theoptic nerve. In these embodiments, the angle b may not be used to reducethe likelihood of exposing the optic nerve to the x-ray. Accordingly,the angles can be used to optimize the treatment plan and present aslittle risk as possible to existing structures that are sensitive toradiation. FIG. 7F depicts eight trajectory angles. In some embodiments,the x-ray trajectory can include less than eight or more than eighttrajectory angles. For example, in some embodiments, four, six, ten, ortwelve trajectory angles are presented. In these embodiments, optimalbeam directions are provided by those beams (e.g., b, a, g, h, f) whichare considered to come from the nasal direction.

The lower picture in FIG. 7F shows the dose on the retina of the angledbeams in the picture above. The predicted isodose fall-off for thesebeams is greater than 90% within 0.05-0.1 mm of a 1-2 mm beam which isless than ten percent. Region 2290 depicts a region of higher dosewithin the iso-dose profile. This higher dose region 2290 results fromthe fact that the beam enters the eye at an angle. The increase in thedose is moderate at approximately ten to twenty percent higher than theaverage for the entire region. Furthermore, because there are multiplebeams entering the eye, the areas of increased dose 2290 average outover the region of the retina. Therefore the higher dose region isincorporated into the treatment plan to account for the unevendistribution.

FIG. 8 is a quantitative, graphical representation of the data in FIG.7. What is shown is the surface to retina dose for different x-ray tubepotentials and for different aluminum filter thicknesses 2385. Thisgraph is the data for beams 2100 and 2140 in FIG. 6. The ratio ofsurface to retina dose is shown in FIG. 8 (i.e., the dose of entry atthe sclera to the dose at the retina); what can be seen is that the doseto the sclera is not more than 3 times the dose to the retina for mostbeam energies (tube potentials). For energies greater than about 40 KVp,the ratio of surface dose to retina dose 2375 is less than about 3:1.What this says is that if the spot were maintained in the same positionas 25 Gy was delivered to the retina, the maximum dose to the sclerawould be 75 Gy. Of course, as the beam is moved around the eye, the 75Gy is averaged over an area and becomes much less than the dose of 25 Gyto the macula. This is depicted in FIG. 6 which shows the results of themovement to different points along the sclera with the x-ray beam. At 80KeVp 2380, the ratio of surface to depth dose is closer to 2.2 with 1 mmof filtering. These data are integrated into the treatment plan and thedesign of system 10 and, in part, determine the time and potential ofthe x-ray tube.

Therefore, in some embodiments, tightly collimated x-ray radiation atenergy levels greater than 40 keV with greater than 1 mm of filtrationdelivered through the pars plana region of the eye can be used todeliver a therapeutic dose of radiation to the retina with a relativelylower dose buildup on the sclera, the lens, or the optic nerve than thetherapeutic dose delivered to the retina. For example, if a therapeuticdose to the retina is 25 Gy or less, the dose to any region of thesclera penetrated by the beam will be less than 25 Gy.

FIG. 9 is a bar graph representation showing scatter doses to ophthalmicregions other than the retina and comparing them to the retina. As canbe seen in the logarithmic figure, the dose to the lens 2400 (beams 2100and 2140) and optic nerve 2410 (beam 2140 alone), the two most sensitivestructures in the eye, are at least an order of magnitude lower than thedose delivered to the macular region 2450 of the retina. Therefore, a 25Gy dose of radiation can be delivered to a region of the retina throughthe pars plana region of the eye with at least an order of magnitudeless radiation reaching other structures of the eye such as the lens,the sclera, the choroids, etc. These simulations dictate the designspecifications for the x-ray generation systems and subsystems. Thesesimulations can also be integrated into the treatment planning system800 as a component of the plan. For example, the planning system, whichincorporates the unique anatomy of each patient, can simulate the amountof radiation delivered to each structure dependent on the angle andposition of delivery through the sclera. Depending on the angle, beamsize, and beam energy, the radiation delivered to the ocular structureswill vary and alternative direction can be chosen if the x-ray dose istoo high to the structures such as the lens and the optic nerve.

To verify the validity of the MC simulations and verify that the eye canbe assumed to be a sphere of water, a human cadaver eye 2500 wasobtained and the ratio of surface to depth dose of an x-ray source wasexperimentally determined. Among other things, parameters of an emittedx-ray beam 2510 were compared with parameters of the beam 2520 emergingfrom the eye 2500. The ratio from the experimental set-up in FIG. 10proved to be identical to that when the eye is assumed to be water inthe MC simulations. For example, the ratio of surface to 2 cm depth for80 KeV with 2 mm filtration was indeed 3:1 as predicted by the MC model.Additional work verified that the dose fall off at each depth waslikewise identical. This experimental work confirms that the modelingpredictions using MC are accurate for ocular structures and thatsecondary interactions typically required of MC simulations with highenergy x-rays are not necessary for lower energy x-rays. Theseobservations significantly simplify the MC simulations and allow forquick real time simulations at the time of treatment planning.Furthermore, the design criteria which are used in the system 10 designcan be accurately modeled using water for their prediction.

Further analysis and experimentation reveals that to deliver 25 Gy tothe macula in a clinically relevant time period (e.g., not longer than30 minutes), the system in FIG. 1 will draw about 1 mA to about 40 mA ofcurrent through the x-ray source. The exact number of mA depends on howclose the x-ray tube is to the eye. If the tube is very close to theeye, then the system will draw less current than if the system isfurther away from the eye. In some embodiments, it may be that the about15 Gy to about 25 Gy needs to be delivered to the retina in a periodshorter than 10 minutes. In such an embodiment, the tube current mayneed to be upwards of 25 mA and the x-ray tube closer than 25 cm fromthe retina. These parameters are for energies of 60-100 KeV and 1-3 mmfiltration with aluminum, lead, tungsten, or another x-ray absorbingmetal. In certain embodiments, the collimator is less than about 5 cmfrom the anterior surface of the eye and the photon energy is about 100KeV with 1, 2, 3, 4, or 5 beams with diameters of between 1 mm and 6 mmentering the eye through the infero-nasal region. The nasal regionaffords the greatest distance from the optic nerve and the inferiorregion is preferred so as to avoid the bones of the nose and theanterior skull. These assumption are for an eye which is positioned tolook straight outward from the skull. In this embodiment, the treatmenttime may be less than about 5 minutes within a range of currents between15 mA and 40 mA. Each beam of the 1-4 beams can be turned on for between3 seconds and 5 minutes. In some embodiments, 3 beams are used for thetreatment. In some embodiments, the collimator is placed within 3 cmfrom the surface of the eye, and in some embodiments, the collimator isplaced within 10 cm of the surface of the eye.

FIG. 11A depicts the results of a collimated x-ray beam 2600 whichpenetrates approximately 2 cm through water (or an eye) 2630 where thecollimator is approximately 5.0 cm from the surface of the water. As canbe seen in FIG. 11A ², there is a small penumbra width 2610 about anoriginal beam width 2620 after penetration through the eye which is lessthan 10% of the shaping beam shown in FIG. 11A ¹. These data incorporateboth divergence as well as isodose drop off and reveal that for acollimator within about 5 cm of the target, the penumbra can be verysmall. FIG. 11B depicts a graphical representation of the penumbra frommeasurements within a film. Delta 2650 represents the absorption in theenergy between the surface and the depth as recorded by x-ray sensitivefilm. The tails seen in 2640 versus 2630 indicate a small degree ofpenumbra effect as the beam loses energy through the eye. Indeed, thepenumbra for a 0.5 mm to 6 mm spot size can be as low as 0.01% and ashigh as ten percent depending on the placement of the collimators withrespect to the eye.

Combination Therapy

Radiotherapy device 10 can be used in combination with othertherapeutics for the eye. Radiotherapy can be used to limit the sideeffects of other treatments or can work synergistically with othertherapies. For example, radiotherapy can be applied to laser burns onthe retina or to implants or surgery on the anterior region of the eye.Radiotherapy can be combined with one or more pharmaceutical, medicaltreatments, and/or photodynamic treatments or agents. As used herein,“photodynamic agents” are intended to have their plain and ordinarymeaning, which includes, without limitation, agents that react to lightand agents that sensitize a tissue to the effects of light. For example,radiotherapy can be used in conjunction with anti-VEFG treatment, VEGFreceptors, steroids, anti-inflammatory compounds, DNA binding molecules,oxygen radical forming therapies, oxygen carrying molecules, porphyrynmolecules/therapies, gadolinium, particulate based formulations,oncologic chemotherapies, heat therapies, ultrasound therapies, andlaser therapies.

In some embodiments, radiosensitizers and/or radioprotectors can becombined with treatment to decrease or increase the effects ofradiotherapy, as discussed in Thomas, et al., Radiation Modifiers:Treatment Overview and Future Investigations, Hematol. Oncol. Clin. N.Am. 20 (2006) 119-139; Senan, et al., Design of Clinical Trials ofRadiation Combined with Antiangiogenic Therapy, Oncologist 12 (2007)465-477; the entirety of both these articles are hereby incorporatedherein by reference. Some embodiments include radiotherapy with thefollowing radiosensitizers and/or treatments: 5-fluorouracil,fluorinated pyrimidine antimetabolite, anti-S phase cytotoxin,5-fluorouridine triphosphate, 2-deoxyfluorouridine monophosphate(Fd-UMP), and 2-deoxyfluorouridine triphosphate capecitabine, platinumanalogues such as cisplatin and carboplatin, fluoropyrimidine,gemcitabine, antimetabolites, taxanes, docetaxel, topoisomerase Iinhibitors, Irinotecan, cyclo-oxygenase-2 inhibitors, hypoxic cellradiosensitizers, antiangiogenic therapy, bevacizumab, recombinantmonoclonal antibody, ras mediation and epidermal growth factor receptor,tumor necrosis factor vector, adenoviral vector Egr-TNF (Ad5.Egr-TNF),and hyperthermia. In some embodiments, embodiments include radiotherapywith the following radioprotectors and/or treatments: amifostine,sucralfate, cytoprotective thiol, vitamins and antioxidants, vitamin C,tocopherol-monoglucoside, pentoxifylline, alpha-tocopherol,beta-carotene, and pilocarpine.

Antiangiogenic Agents (AAs) aim to inhibit growth of new blood vessels.Bevacizumab is a humanized monoclonal antibody that acts by binding andneutralizing VEGF, which is a ligand with a central role in signalingpathways controlling blood vessel development. Findings suggest thatanti-VEGF therapy has a direct antivascular effect in human tissues. Incontrast, small molecule tyrosine kinase inhibitors (TKIs) preventactivation of VEGFRs, thus inhibiting downstream signaling pathwaysrather than binding to VEGF directly. Vascular damaging agents (VDAs)cause a rapid shutdown of established vasculature, leading to secondarytissue death. The microtubule-destabilizing agents, includingcombretastatins and ZD6126, and drugs related to5,6-dimethylxanthenone-4-acetic acid (DMXAA) are two main groups ofVDAs. Mixed inhibitors, including agents such as EGFR inhibitors orneutralizing agents and cytotoxic anticancer agents can also be used.

Radiodynamic Therapy

Radiodynamic therapy refers to the combination of collimated x-rays witha concomitantly administered systemic therapy. As used herein, the term“radiodynamic agents” is intended to have its ordinary and plainmeaning, which includes, without limitation, agents that respond toradiation, such as x-rays, and agents that sensitize a tissue to theeffects of radiation. Similar to photodynamic therapy, a compound isadministered either systemically or into the vitreous; the region in theeye to be treated is then directly targeted with radiotherapy using theeye model described above. The targeted region can be preciselylocalized using the eye model and then radiation can be preciselyapplied to that region using the PORT system and virtual imaging systembased on ocular data. Beam sizes of 1 mm or less can be used inradiodynamic therapy to treat ocular disorders if the target is drusenfor example. In other examples, the beam size is less than about 6 mm.

While certain aspects and embodiments of the disclosure have beendescribed, these have been presented by way of example only, and are notintended to limit the scope of the disclosure. Indeed, the novel methodsand systems described herein may be embodied in a variety of other formswithout departing from the spirit thereof. The accompanying claims andtheir equivalents are intended to cover such forms or modifications aswould fall within the scope and spirit of the disclosure.

1-22. (canceled)
 23. A treatment system, comprising: an eye contactmember, configured to contact an outer surface of an eye, the eyecontact member comprising a fiducial marker; a radiation source,configured to emit a beam of radiation; and a control system configuredto (i) identify a mapped location, based on imaging data, of a targetregion within the eye relative to a location of the fiducial marker and(ii) position, based on the mapped location, the radiation source todirect the beam to the target region.
 24. The treatment system of claim23, wherein the target region comprises a macula of the eye.
 25. Thetreatment system of claim 23, wherein the radiation source is coupled toa collimator.
 26. The treatment system of claim 23, wherein theradiation source is configured to emit the beam with a cross-sectionalwidth of less than about 6 mm.
 27. The treatment system of claim 23,wherein the control system is operably connected to an electromechanicalactuation system for positioning the radiation source.
 28. The treatmentsystem of claim 23, wherein the control system is operably connected toa wheel or shaft for positioning the radiation source.
 29. The treatmentsystem of claim 23, wherein the control system is operably connected toa shutter system for controlling emission of the beam.
 30. The treatmentsystem of claim 23, wherein the control system is further configured todetect a movement of the eye.
 31. The treatment system of claim 23,further comprising an additional radiation source, configured to emit anadditional beam of radiation.
 32. The treatment system of claim 23,wherein the radiation is x-ray radiation.
 33. The treatment system ofclaim 23, wherein the outer surface of the eye is a cornea.
 34. Thetreatment system of claim 23, wherein the outer surface of the eye is asclera.
 35. The treatment system of claim 23, wherein the eye contactmember is configured to apply suction to the eye.
 36. The treatmentsystem of claim 23, wherein the eye contact member comprises anadditional fiducial marker.
 37. The treatment system of claim 23,wherein the imaging data is a product of computed tomography, magneticresonance imaging, optical coherence tomography, positron emissiontomography, interferometry, ultrasonography, scanning laserophthalmoscopy, x-ray imaging, or magnetic resonance imaging
 38. Atreatment system, comprising: an eye contact member, configured tocontact a cornea or sclera of an eye, the eye contact member comprisinga fiducial marker; an x-ray radiation source, configured to emit a beamof x-ray radiation; and a control system configured to (i) identify amapped location, in a coordinate system and based on imaging data, of atarget region of a macula within the eye relative to a location of thefiducial marker and (ii) position, based on the mapped location, theradiation source to direct the beam to the target region.
 39. Thetreatment system of claim 38, wherein the radiation source is coupled toa collimator.
 40. The treatment system of claim 38, wherein theradiation source is configured to emit the beam with a cross-sectionalwidth of less than about 6 mm.
 41. The treatment system of claim 38,wherein the control system is operably connected to an electromechanicalactuation system for positioning the radiation source.
 42. The treatmentsystem of claim 38, further comprising an additional x-ray radiationsource, configured to emit an additional beam of x-ray radiation.